CA1216284A - Thiazolylacetamido compounds - Google Patents
Thiazolylacetamido compoundsInfo
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- CA1216284A CA1216284A CA000242004A CA242004A CA1216284A CA 1216284 A CA1216284 A CA 1216284A CA 000242004 A CA000242004 A CA 000242004A CA 242004 A CA242004 A CA 242004A CA 1216284 A CA1216284 A CA 1216284A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Thiazolylacetamido compounds Abstract of the Disclosure Novel cephem compounds of the formula;
Description
~ 2~ 24205-320 The present invention relates to cephem compounds of the formula: .
N ~- CONH ~ ~ S (I) O
COOH
(wherein Rl represents amino or hydroxyl group which may be protected; A represents -CH-, -C~- or a group of the formula
N ~- CONH ~ ~ S (I) O
COOH
(wherein Rl represents amino or hydroxyl group which may be protected; A represents -CH-, -C~- or a group of the formula
2 OH
>C=NR5 wherein R5 is hydroxyl or a protected hydroxyl group;
R3 represents hydrogen or methoxy; R15 represents 2-carboxy-ethenyl~ chloro or methoxy group or represents C1~2R ; Rl represents i) hydrogen, ii) hydroxyl, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) carbamoyloxy, ~iii) carbamoyl-thio, ix) thiocar~amoyloxy, x) any group o~ ii) to ix) substituted with alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulEonYloxY, xvi) (cis-1,2-epoxypropyl~phosphono or xvii) a group of the formula -S-R wherein R is a 5- or 6-m~mbered hetero ring containing one to four hetero atoms selected ~rom the group consisting of oxygen, sulfur and nitrogen; and R8 represents hydrogen~,or pharmaceutically acceptable salts or esters thereof.
The present inventors, after extensive research ~0 succeeded in synthesizing novel cephem compounds (I) and have found that the cephem compounds (I) have strong antibiotic properties against a wide variety of microorganisms including gram-positive bacteria as well as gram-negative ones, especially by oral administration and that the cephem compounds (I) can be used as therapeutic agent for various bacterial infections of animals including human beings.
The present invention also relates to a process for preparing the cephem compounds (I) or a pharmaceutically acceptable salt or ester thereof. The process comprises (1) n reacting a compound of the formula:
2 ~ R15 (VI) COOH
(wherein R3 and R15 are as defined above), or a salt or ester thereof, with a compound of the formula:
Rl S R8 (V) N A'~COO~
(wherein Rl and R8 are as defined above and A' represents any of the radicals as defined for A except that the amino or hydroxyl groups may be protected), or a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or (2) for preparing a compound of the formula (I) in which A represents -CH-, or a pharmaceutically acceptable salt or ester thereof, reducing a compound of the formula:
Rl R8 R~ (VII) ~L
NR O
COOH
(wherein R , R3, R5, R8 and R have the same meanings as defined above) or a salt or ester thereof, followed by, if necessary, removal of any protective groups; or (3) for prepar-ing a compound of the formula (I) in whlch R15 is CH2R4 and R4 is other than acyloxy, carbamoyloxy and hydrogen, or a pharmaceutically acceptable salt or ester thereof, reacting a compound of the formula:
,R3 S
A'-CONH I ~ ~ (IX) N ~ CH2 COOH
(wherein R6 represents an acyloxy, carbamoyloxy group or a halogen and A', Rl, R3 and R8 have the same meanings as deined above) or a salt or ester thereof, with a tertiary amine or a compound of the formula: R '-H wherein R ' represents any of the radicals a~ defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, ~2~
followed by, if necessary, removal of any protective groups;
and where required converting any free carboxylic acid of the formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or estex of a compound (I) in~o the free carboxylic acid.
In the cephem compounds (I), the symbol R represents amino or hydroxyl group, or protected amino or hydroxyl group. The protected amino group means an amino group protected with such easily removable protective groups of amino group as usually employed in the peptide chemistry, which are exemplified by an alkylcarbonyl group such as formyl, acetyl, propionyl, etc., an alkoxycarbonyl group such as t-butoxy-carbonyl, etc., an alkoxyalkylcarbonyl group such as methoxyacetyl, methoxypropionyl, etc., a substituted alkoxycarbonyl group such as trichloroethoxycarbonylr etc., a substituted alkylcarbonyl such as monochloromethylcarbonyl, monochloroethylcarbonyl, dichloromethylcarbonyl, dichloro-ethylcarbonyl, trichloromethylcarbonyl, trichloroethylcarbonyl, trichloropropylcarbonyl, etc., an aralkyloxycarbonyl group such as benzyloxycarbonyl, etc., a substituted aralkyloxycarbonyl group such as p-nitrobenzyloxycarbonyl, etc. or amino group protected with proton. The protected hydroxyl group means a hydroxyl group protected with easily removable protective group of hydroxyl group. Such easily removable protective group of hydroxyl group may be exemplified by e.g. an acyl ~2~
group such as formyl, acetyl, chloroace-tyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl, e-thoxycarbonyl, ~,3,~-trichloroe-thoxycarbonyl,
>C=NR5 wherein R5 is hydroxyl or a protected hydroxyl group;
R3 represents hydrogen or methoxy; R15 represents 2-carboxy-ethenyl~ chloro or methoxy group or represents C1~2R ; Rl represents i) hydrogen, ii) hydroxyl, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) carbamoyloxy, ~iii) carbamoyl-thio, ix) thiocar~amoyloxy, x) any group o~ ii) to ix) substituted with alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulEonYloxY, xvi) (cis-1,2-epoxypropyl~phosphono or xvii) a group of the formula -S-R wherein R is a 5- or 6-m~mbered hetero ring containing one to four hetero atoms selected ~rom the group consisting of oxygen, sulfur and nitrogen; and R8 represents hydrogen~,or pharmaceutically acceptable salts or esters thereof.
The present inventors, after extensive research ~0 succeeded in synthesizing novel cephem compounds (I) and have found that the cephem compounds (I) have strong antibiotic properties against a wide variety of microorganisms including gram-positive bacteria as well as gram-negative ones, especially by oral administration and that the cephem compounds (I) can be used as therapeutic agent for various bacterial infections of animals including human beings.
The present invention also relates to a process for preparing the cephem compounds (I) or a pharmaceutically acceptable salt or ester thereof. The process comprises (1) n reacting a compound of the formula:
2 ~ R15 (VI) COOH
(wherein R3 and R15 are as defined above), or a salt or ester thereof, with a compound of the formula:
Rl S R8 (V) N A'~COO~
(wherein Rl and R8 are as defined above and A' represents any of the radicals as defined for A except that the amino or hydroxyl groups may be protected), or a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or (2) for preparing a compound of the formula (I) in which A represents -CH-, or a pharmaceutically acceptable salt or ester thereof, reducing a compound of the formula:
Rl R8 R~ (VII) ~L
NR O
COOH
(wherein R , R3, R5, R8 and R have the same meanings as defined above) or a salt or ester thereof, followed by, if necessary, removal of any protective groups; or (3) for prepar-ing a compound of the formula (I) in whlch R15 is CH2R4 and R4 is other than acyloxy, carbamoyloxy and hydrogen, or a pharmaceutically acceptable salt or ester thereof, reacting a compound of the formula:
,R3 S
A'-CONH I ~ ~ (IX) N ~ CH2 COOH
(wherein R6 represents an acyloxy, carbamoyloxy group or a halogen and A', Rl, R3 and R8 have the same meanings as deined above) or a salt or ester thereof, with a tertiary amine or a compound of the formula: R '-H wherein R ' represents any of the radicals a~ defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, ~2~
followed by, if necessary, removal of any protective groups;
and where required converting any free carboxylic acid of the formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or estex of a compound (I) in~o the free carboxylic acid.
In the cephem compounds (I), the symbol R represents amino or hydroxyl group, or protected amino or hydroxyl group. The protected amino group means an amino group protected with such easily removable protective groups of amino group as usually employed in the peptide chemistry, which are exemplified by an alkylcarbonyl group such as formyl, acetyl, propionyl, etc., an alkoxycarbonyl group such as t-butoxy-carbonyl, etc., an alkoxyalkylcarbonyl group such as methoxyacetyl, methoxypropionyl, etc., a substituted alkoxycarbonyl group such as trichloroethoxycarbonylr etc., a substituted alkylcarbonyl such as monochloromethylcarbonyl, monochloroethylcarbonyl, dichloromethylcarbonyl, dichloro-ethylcarbonyl, trichloromethylcarbonyl, trichloroethylcarbonyl, trichloropropylcarbonyl, etc., an aralkyloxycarbonyl group such as benzyloxycarbonyl, etc., a substituted aralkyloxycarbonyl group such as p-nitrobenzyloxycarbonyl, etc. or amino group protected with proton. The protected hydroxyl group means a hydroxyl group protected with easily removable protective group of hydroxyl group. Such easily removable protective group of hydroxyl group may be exemplified by e.g. an acyl ~2~
group such as formyl, acetyl, chloroace-tyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl, e-thoxycarbonyl, ~,3,~-trichloroe-thoxycarbonyl,
3,~,3-tribromoethoxycarbonyl, p-nitrophenoxycarbonyl, etc., an easily removable protective group under relatively mild conditions such as tetrahydropyranyl, tetrahydro-thiofuranyl, methoxytetrahydropyranyl, etc. The symbol A may represent -CH- or -CH ,and the symbol A' represents any of the radicals as defined for A except that the amino or hydroxyl groups may be protected. The protected amino or hydroxyl groups in A' include those protected amino or hydroxyl groups mentioned above, and the suitable examples thereof are the same as that of the protected amino or hydroxyl group as mentioned in the symbol Rl. ~ and A' also represent a group of the formula:
>C=NR5 wherein RS is hydroxyl group which may be protected. As the protective group of this hydroxyl group, -there may be generally employed a lower alkyl group such as methyl, ethyl, etc., an aryl group such as phenyl, thienyl, etc., an acyl group such as acetyl, benzoyl, etc. In case of A being a~roup of the formula; >C=NR5, the cephem compounds (I) are shown by the formula:
J~l .
~216;~34 _ ~ R (XXI) N CCONH- ~ R15 R COOH
wherein the symbols have the same meaning as defined above.
The symbol R3 means hydrog~n or methoxy group. The symbol R represents hydrogen. The substituents at 3-position of the cephem compounds(i.e., -R15),include 2-carboxyethenyl, chloro, methoxy and a radical of the formula: -CH2R4.
When R3 means hydrogen and R15 means the radical of the formula: -CH2R4, the cephem compounds (XXI) are shown by the formula:
R ~ S H H
N ~ C-CONH ~ S 1 (XXI-a) N ~ N ~ CH2R
R4 can be (i) hydrogen, or a residue oE a nucleophilic com-pound~ The residue of nucleophilic compound shown by the symbol R4 may be exemplified by (ii) hydroxyl which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.); (iii) mercapto which may optionally be ~2~ 8~
substitu-ted with alkyl (e.g. methyl, ethyl, propyl, etc.); (iv) cyano; (v) azido; (vi) amino which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.) such as N-methylamino, N,N-dime-thylamino, N-ethylamino, N,N-diethylamino, N-propylamino, etc.; (vii) carbamoyloxy which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.);
(viii) carbamoylthio which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl etc.); or (ix) thiocarbamoyl-oxy group which may optionally be substituted with alkyl (e.g.
methyl, ethyl, propyl, etc.); (xi) acyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, benzoyloxy, p-chlorobenzoyloxy, p-methylbenzoyloxy, etc.); (xii) a tertiary ammonium group;
(xiii) hydroxyphenyl; (xiv) sulfamoyloxy; (xv) alkylsulfonyloxy;
(xvi) (cis-1,2-epoxypropyl)phosphono; or (xvii) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen. The hetero ring is exemplified by a 6-membered nitrogen-containing hetero ring e.g~ pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, etc. a 5-membered nitrogen-containing he-tero ring e.g. pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetr-azolyl, 2H-tetrazolyl, etc. and others. Each of -these hetero ~L2~134 ring may b~ further substituted and, as the subs-tituents, there may be mentioned for example, lower alkyls such as methyl, ethyl, propyl, etc., lower alkoxyls such as methoxy, ethoxy, etc., halogens such as chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl group, etc.
The tertiary ammonium group represented by R may be exemplified by e.g. pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3-iodopyridinium,
>C=NR5 wherein RS is hydroxyl group which may be protected. As the protective group of this hydroxyl group, -there may be generally employed a lower alkyl group such as methyl, ethyl, etc., an aryl group such as phenyl, thienyl, etc., an acyl group such as acetyl, benzoyl, etc. In case of A being a~roup of the formula; >C=NR5, the cephem compounds (I) are shown by the formula:
J~l .
~216;~34 _ ~ R (XXI) N CCONH- ~ R15 R COOH
wherein the symbols have the same meaning as defined above.
The symbol R3 means hydrog~n or methoxy group. The symbol R represents hydrogen. The substituents at 3-position of the cephem compounds(i.e., -R15),include 2-carboxyethenyl, chloro, methoxy and a radical of the formula: -CH2R4.
When R3 means hydrogen and R15 means the radical of the formula: -CH2R4, the cephem compounds (XXI) are shown by the formula:
R ~ S H H
N ~ C-CONH ~ S 1 (XXI-a) N ~ N ~ CH2R
R4 can be (i) hydrogen, or a residue oE a nucleophilic com-pound~ The residue of nucleophilic compound shown by the symbol R4 may be exemplified by (ii) hydroxyl which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.); (iii) mercapto which may optionally be ~2~ 8~
substitu-ted with alkyl (e.g. methyl, ethyl, propyl, etc.); (iv) cyano; (v) azido; (vi) amino which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.) such as N-methylamino, N,N-dime-thylamino, N-ethylamino, N,N-diethylamino, N-propylamino, etc.; (vii) carbamoyloxy which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl, etc.);
(viii) carbamoylthio which may optionally be substituted with alkyl (e.g. methyl, ethyl, propyl etc.); or (ix) thiocarbamoyl-oxy group which may optionally be substituted with alkyl (e.g.
methyl, ethyl, propyl, etc.); (xi) acyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, benzoyloxy, p-chlorobenzoyloxy, p-methylbenzoyloxy, etc.); (xii) a tertiary ammonium group;
(xiii) hydroxyphenyl; (xiv) sulfamoyloxy; (xv) alkylsulfonyloxy;
(xvi) (cis-1,2-epoxypropyl)phosphono; or (xvii) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen. The hetero ring is exemplified by a 6-membered nitrogen-containing hetero ring e.g~ pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, etc. a 5-membered nitrogen-containing he-tero ring e.g. pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetr-azolyl, 2H-tetrazolyl, etc. and others. Each of -these hetero ~L2~134 ring may b~ further substituted and, as the subs-tituents, there may be mentioned for example, lower alkyls such as methyl, ethyl, propyl, etc., lower alkoxyls such as methoxy, ethoxy, etc., halogens such as chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl group, etc.
The tertiary ammonium group represented by R may be exemplified by e.g. pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3-iodopyridinium,
4-carbamoylpyridinium, 4-(N-hydroxymethylearbamoyl)pyridinium, 4-(N-carbomethoxyearbamoyl)pyridinium, 4-(N-cyanocarbamovl)-pyridinium, 4-(carboxymethyl~pyridinium, 4 (hydroxymethyl)-pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium, lutidium, etc. The carboxyl group at 4-position of the cephem rin~ may be free type, or salts with nontoxic cation such as sodium, potassium or the like; a basic amino acid such as arginine, ornithine, lysine, histidine or the like; or a polyhydroxyalkylamine such as N-methyl~lucamine, diethanol-amine, triethanolamine, trishydroxymethylaminomethane or the li.ke.
~0 ~lternatively, the earboxyl group may be a biologically active ester derivative, said ester derivatives being conducive to, for instance, an increased blood level or/and a longer duration of activity. As the ester residues of use for this purpose, there may be mentioned, for example, alkoxymethyl and ~-alkoxyethyl , ~6Z84 and other ~-alkoxy-~-substituted methyl ~roups, e.g. methoxy-methyl, ethoxymethyl, isopropoxymethyl, ~-methoxyethyl, ~-ethoxyethyl, e-tc.; alkylthiomethyl groups, e.g. methylthio-methyl, ethylthiomethyl, isopropylthiome-thyl, etc.; and acyloxymethyl and ~-acyloxy-~-substituted methyl groups, e.g.
pivaloyloxymethyl, ~-acetoxybutyl, etc.
Thus, the preferable examples of the present cephem compounds (I) may be the compounds that the group Rl means methyl, acetoxymethyl, (l-methyl-tetrazol-5-yl)thiomethyl, (1,2,3-triazol-5-yl)thiomethyl, (2-methyl-1,3,4-thiadiazol-5-yl)~hiomethyl, etc. These compounds (I) are all novel and useful as antibiotics. Like the known cephalosporins or penicillins, the contemplated compounds (I) of this invention can each be administered in the forms of injection, capsules, tablets, granules, solutions, suspensions, solid forms, if necessary, with a physiologically acceptable carrier or excipient in accordance with the established pharmaceutical procedure. The contemplated compounds of this invention, such as sodium 7~-methoxy-7~-(2-aminothiazol-4-ylglycylamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid may be injected intramuscularly at a daily dose level of about 5 to 20 mg./kg. human body weight in 3 to 4 divided dose per day and are effective against respiratory-organ infections, : ~`
~6~8~
urinary-trac-t infec-tions, etc. And, the compounds (I) show strong antibiotic properties against a wide variety of microorganisms including gram-positive or negative bacteria, even by oral administration.
A process for producing the compound of formula (XXI-a) or a pharmaceutically acceptable salt or ester thereof, comprises:
(1) reacting a compound of the formula:
H2N ¦ ~ ~ (VI-a) O~ -N ~ CH2 COOH
wherein R4 is as defined above, or a salt or ester of the compound (VI-a), with a compound of the formula:
N C-COOH (V-a) N
wherein Rl and R5 are as defined above, or a reactive derivative of the acid (V-a), and where necessary, removing the amino-protecting group which may be present in the radical Rl of the obtained product to give a compound of formula (XXI-a) wherein R is an amino group, or (2) reacting a compound of the formula:
~Z~6ZI~
R
N ~ C-CONH - ~ ~ S (IX-a) N O N ~ c~2 R COOH
wherein R6 represents an acyloxy or carbamoyloxy group or a halogen atom, and R and R are as defined above, or a salt or ester of the compound (IX-a), with a tertiary amine or a compound of the formula: R '-H wherein R ' represents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, and where required, removing the amino-protecting group which may be present in the radical Rl in the obtained compound to give a compound of formula (XXI-a) wherein R is an amino group, and if desired, converting any free carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into a pharmaceutically acceptable salt or ester thereof, or converting any salt or ester of the carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into the free acid or into a pharmaceutically acceptable salt or ester thereof.
Preferred condi-tions of the reactions for producing cephem compounds (I)(including compounds ~XXI) and (XXI-a) where applicable)of the present invention are described below.
(a) Reaction o~ compounds (V)(or (V-a))and (VI)(or (VI-a~).
~, , 1 1 --,~ .
~l6~
The carboxyl group of the starting compounds (VI) of this reaction may be used as a salt form with alkali me-tals, organic amines such as sodium, potassium, triethylamine, etc., or as an ester form which can be easily converted into free carboxyl group by mild treatment with an acid or alkali, or by reduction, the ester being exemplified by e.g. wi-th ~-methyl-sulfonylethyl, trimethylsilyl, dimethylsilenyl, benzhydryl, ~ trichloroethyl, phenacyl, p-methoxybenzyl, p-nitrobenzyl, methoxymethyl, etc. As the reactive derivatives of the other starting compounds (V), there may be employed acid halide, acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide, ester, etc., thereof.
This reaction can be conducted advanta~eously and smoothly in the presence of a solvent. As said solvent, use may be made of the common solvents and their mixtures unless such solvents do not interfere with the present reaction. There may be mentioned, therefore, such solvents as water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloro-methane, dichloroethylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc- This reaction may proceed more advantageously when in the solvent there is added a base such as pyridine, triethylamine, N,N-dimethylaniline, sodium hydrogen carbonate, etc.
- lla -~``/ . , ~Z~28~
The quantity of the base to be added is 100-~00 ~, desirably 100-c'OO /0 of that of the starting compounds (V). While the reaction temperature is virtually optional~ the reaction usu~lly is carried out under cooling or at room tempera-ture The reaction is generally completed within sever~l minutes to several hours.
If necessary, thus obtained compounds are subjec-ted to removal of the proteetive group and/or conversion of the convertible group~ The removal of the proteetive group of amino group may be conducted, for example, by acid trea-tment for t-buto~-ycarbonyl, ete., by a trea-tment with zine and an acid for P,'-', J ~-triehloroethoxycarbonyl~ e-tcO by catalytie reduction for p--nitrobenzyloxycarbonyl, etc The protective groups of hydroxyl group are removed, for example, by potas-sium hydrogen carbonate in aqueous methanol for formyl or trifluoroacetyl, etc., by diluted hydrochloric aeid treat-ment, for tetrahydropyrclnyl~ etc., by zine and an aeid treat-men-t for ~"'"~-triehloroethoxyearbonyl, e-tc The es-ter residues of the earboxylie aeids are removed, for ex~mple, by aeid treatment :~`OI` ben~hyclryl, p-methoxybenzyl, etc., by alkali treatment for ~-methylsulfonylethyl, ete., by aqueous treat~ent for trimethylsilyl, dimethylsilenyl, etc., by zinc-an aeid tre~tment for ~ -trichloroethyl eteO, by redue-tion for p-nitrobenzyl, ete The methylthio or methyl-seleno group e-tc. may be eonverted into methoxy group by e.g~ reacting methanol iIl the presence of metal compounds including silver, mercury, leaci, thallium, etc. The removal of the protective ~roups or the conversion of the groups 8~
may be performed at the same time if possible, or any of them may be removed or converted in accordance with -the sort of the groups and/or the reaction condition of the next step.
While the starting carboxylic acids (V) may occur as D- and L-isomers with respect to the ~-carbon, whichever of these isomers, as well as their mixture, can be successfully employed for the purposes of this invention. It is known that generally, of cephalosporins or penicillins having a center of asymmetry at ~-position, D-isomers are more antibiotic than the L-isomers.
The compounds (V) employed as the starting materials in this reaction may be prepared by the processes which will be mentioned just below and are used in that condition obtained by these processes or after removal of the protecting groups and/or conversion of the groups.
A compound of the formula:
~ (XI) N CHCOOH
(wherein the symbols have the same meanings as defined above), which is within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reducing a compound of the formula:
~2~ Z~3~
Rl R8 B ~ (IV) N CCOOH
NR
(wherein R5 represents hydroxyl group which may be protected and each of other symbols has the same meaning as defined above), or a salt or ester thereof, followed by, if necessary, removal of the protective group.
A compound o~ the formula:
~ (XIV) N C-COOH
Y Z
(wherein R represents amino or hydroxyl which may be protected and other symbols have the same meanings as defined below), which is also within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting a compound of the formula:
XCH2 - C - C - COOH (XII) Il /\
O Y Z
(wherein X means a halogen and, when Y is hydrogen, Z means amino group which may be protected or Y and Z together represent a group of the formula:
=NR5 (R5 is hydroxyl group which may be protected)), or a salt or ester thereof, and a compound of the formula:
-- 1~ --2~3~
R - C - NH2 (XIII) (wherein R13 represents a lower alkoxy group or amino group which may be protected), followed by, if necessary, removal of the protective group.
A compound of the formula:
HO ~ S
N ~ C-COOH (XVI) NR
(wherein the symbol has the same meaning as defined above) which is also within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting a compound of the formula:
H2N b,~L
N C-COOH (XV) NR
(wherein the symbol has the same meaning as defined above), or a salt or ester thereof, with a diazotizing reagent.
A compound of the formula:
1~
R ~ ~ (XIX) N CH-COOH
OH
~2~284 (wherein the symbol has the same meaning as defined below) which is within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting A compound of the formula: S
R - C - NH2 (XVII) (wherein R14 represents amino group which may be protected), with trihalogenoacetone in the presence of a base to obtain a compound of the formula:
(XVIII) N CHO
(wherein the symbol has the same meaning as defined above), subjecting the compound (~VIII) to addition reaction of hydrogen cyanide and hydrolyzing thus obtained product, followed by, if necessary, removal of the protective group.
(b) Reduction of the compounds (VII) In the starting compounds (VII), the symbols other than R5 have the same meanings as defined above, and symbol R5 means hydroxyl group which may be protected. As the protect-ive groups of hydroxyl group, any oE the conventional ones may be used so far as they do not disturb the reactions of this invention and there may be generally employed a lower alkyl group such as methyl, ethyl, etc., an aryl group such as phenyl, thienylr etc., an acyl group such as acetyl, benzoyl, etc.
The reduction condition employed in the present reaction may be selected from the known reduction methods so ~ ~ - 16 -,.
~Z;3 ~84 far as the compounds tVII) can be reduced into the compounds (VIII), namely the compounds (I) wherein -A- represents -CH- , N~12 and preferable ones are the catalytic reduction employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., reduction means employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam, etc. and water, alcohols, etc. reduction means employ-ing metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, etc., reduction means treating with metals such as zinc, iron, etc. in solvents such as acetic anhydride, formic acid, or aqueous mixture thereof, etc., electroreduction, etc.
The reaction conditions such as reaction temperature, pressure, sort of the solvents, reaction time, and others are selected suitably according to the sort of starting materials, reduction means, etc. After the reduction reaction, the reaction mixture may be, if necessary, subiected to removal reaction o-f the protective group directly or after separation of the objective compounds (VIII). The removal of the protective group is conducted in accordance with the conventional removing methods employed for the removal of each protective group.
(c) Reaction of the compounds (IX) or (IX-a) with a nucleo-philic compound~
- 16a -~16;2~
In the compounds tIX), the symb~l R6 represents carbamoyloxy, an acyloxy such as acetyloxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyloxy, 2-carboxybenzoyloxy, 4-carboxybutyryloxy, mandelyloxy, 2-(carboethoxycarbamoyl)-benzoyloxy, 2-(carboethoxysulfamoyl)benzoyloxy, 3-ethoxy-carbamoylpropionyloxy, etc., a halogen such as bromine, chlorine, etc. and among them the acyloxy groups are generally employed.
The nucleophilic compounds correspond to the compounds having the symbol R of the compounds (I) mentioned above, except for hydrogen, carbamoyloxy, acyloxy and tertiary ammonium. Among the nucleophilic compounds, the mercapto compounds are reacted each in such forms as the free compound or a salt with an alkali metal such as sodium, potassium or the like. This reaction is desirably conducted in a solvent. For example, use can be made of water, heavy water or organic solvents readily miscible with water and inert to the starting compounds, such as dimethylformamide, dime-thylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfoxide, tetrahydrofuran, etc.
The reaction temperature and time depend, among other factors, upon the starting compounds, solvent, etc. to be employed but ~enerally the reaction is carried out at a selected temperature within the ran~e of 0 to 100C for a selected time of a few hours to several days. The reaction is desirably conducted in the neighborhood of neutrality or between pH 2 and 8 and, for better results, between pH 5 and 8. The reaction often proceeds more smoothly by the addition of a quaternary ammonium salt - 16b -` . `
6~34 having surface active effect (e.g. -trimethylbenzylammonium bromide, triethylbenzylammonium bromide, -triethylbenzylammonium hydroxide, etc.) to the reaction system. To prevent oxidation of the mercapto compounds, it is advantageous to carry out the reaction in an inert gaseous atmosphere, e.g. nitrogen gas.
The cephem compounds (I) obtained by the processes illustrated hereinbefore, can be purified by such procedures as column chromatography, extraction, precipitation, recrystall-ization, etc. The compounds (I), if desired, are further converted to contemplated salt or ester, etc. by a per se known process.
When A represents a group of the formula: ~C=NR , the compound (IX) may be represented by the formula:
R \ f S ~ ,R3 N ll C-CONH ~ S ~ (XX) NR5 ~ N ~ CH2R
COOH
which may be reacted with nucleophilic compounds under similar conditions mentioned above.
Each starting compound employed in the above mentioned processes for preparing the cephem compounds (I) can be prepared for example by the following processes.
(d) Reduction of the compounds (IV) Similar reduction conditions as mentioned in above - 16c -~Z~Z8~
(b) are employed in this reaction. Thè~carboxyl group of the starting compounds (IV) may be protected with a protective group removable under mild conditions which will not interfere with the thiazole ring, for example by acid or ; - 16d -~Z~L~28~
alkaline condi-tiOn reduction etc Therefore, such pro-tec-tive groups may-be selected from those of carbo~yl group generally employed in the peptide synthesis and are exempli-fied by alkali metals such as sodium, potassium, e-tc alkyl such as me-thyl~ ethyl, propyl, isopropyl, butyl, sec-butyl, isobu-tyl, tert-butyl, etc., substituted alkyl such as ~-methylsulfonylethyl, trichloroethyl 7 diphenyl-methyl, etc , aryl such as phenyl, tolyl, etcO, substituted aryl such as p--tert-butylphenyl, p-ni-trophenyl, etc., aralkyl such as benzyl, phenethyl, tolubenzyl~ etc., substituted aralkyl such as p-me-thoxybenæyl~ p-ni-trobenzyl, e-tc. In the present reaction, it seems that the starting compound ~IV) wherein ~5 is protected hydroxyl~ gives better result. The contemplated compounds ~V) may be purified by a per se known purification method such as solvent extraction, pH adjustment, crystalliæation, recrystallization, distillation, chromatography, ion-exchange chromatography, etc. The isolated compound ~) is ~L-mi~ture and may be resolved into D-foxm and ~-form respectively by introducing it to suitable op-tical-ac-tive-crystal-formin~ salt, e g.salt wi-th tartaric acid, mandelic acid, malic acid, camphor-sul~onic acid, etc.
(e) ~eaction of the compounds (XII) wi-th (~
In the starting compounds (XII), the symbol X means halogen such as chlorine, bromine, iodine~ fluorine, etc.
When Y represents hydrogen~ Z means amino group which may be protec-ted, such ~roup being exemplified above ~lter-natively, Y and Z toge-ther represent a group of the formula;
~L6284 =N~-, such group bein~ also illu~trated above, The carboxyl ~roup of the compounds (XII) may be protected in a similar manner to that mentioned in respect of the cGmpounds (:[V). In the present reaction~ it is desirflble to reac-t substantially equivalent mole of both the starting com,ounds (XII) and (XIII)o The reaction is generall~J
conducted in the solvent and such solvent may be selected from the organic solvent which ~Jill not disturb the contemp-lated reaction. Thus, methanol, ethanol, propanol 7 tetra-hydrofuran, for example~ are suitably employe~ The reac-tion is carried out smoothly at room temperature or under reflux condition. The reaction is generally comple-ted within one to several hoursO The reaction may ~e carried out more smoothly by adding base such as dimethylaniline triethylamine1 etc, to the reaction systemO ~fter the reaction i~ completed~ the removal of the protecting g:roup may be conducted directly to the reaction mixture or after isolation of the compoullds (XIV), if desired, The purification of the compounds tXI~') may be carried out by the similar means as mentioned above (d)o When the starting compounds ~III) wherein R13 represents a lower alko~y ~roup are employed~ there is obtained a contemplated compound (~IV) wherein Rl is hydroxyl according to the present reaction, (f) Dia~otization of -the compounds (XV) The carboxylic ~roup o~ the starting compounds (XV) employed in this reaction may be protected by the similar manner as mentioned in the above compounds (IV). The ~6~84 reaction is generally conducted in a solvent, for example, water or a mixture of wa-ter and organic solven-ts which are readily rniscible with water and do not disturb the present reaction such as alcohols e,g, methanol, e-thanol, etc,~
ethers e,g, tetrahydrofuran~ dioxane, etcO As the diazo-tization reagents, nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, etc, are conveniently employed and, among them, sodium nitrite1 amyl nitrite, etc. are generally used. The reaction is generally conducted in the presence of an acid at a selected temperature within the range of O to 50C for a selected time of one to several hours, The acid employed in the reaction is exemplified by hydrochloric acid, sulfuric acid 9 phosphoric acid, formic acid, acetic acid, etc, While ~-oximino-2-substituted-thiazol-~-ylacetic acid derivatives involved in these compounds (XIV) and lX~I) may occur theoretically as syn- and anti-isomer with res-pec-t to oximino group, each of the both isomers can be used, similarly for -the present reactionO
(~) Reaction o~ the compounds (XVII) and trihcllogenoacetone The symbol R14 represents such amino group which may be protected as illustrated hereinbefore and, therefore~
the com~ounds (XVII~ are exemplified by N-(trichloroethoxy-carbonyl)thiourea, N-(t-butoxycarbonyl)thiourea, N-(benzyl-oxycarbonyl~thiourea, etc~ As the trihalogenoace-tone, there are generally used, for example, lS1,3-trichloro-acetone, l,l,~-tribromoacetone, etc.
The reaction may be carried ou-t advantageously in 3l6;2~
the solvent. ~ny solvent which can dissolve both s-tarting materials may be employed so far as it does not dis-turb the reaction, and more preferably one is exemplified by alcohols such as methanol, e-thanoll propanol, etc , ke-tones such as acetone, methyl ethyl ~etone, etcO, ethers such as ether, tetrahydrofuran, dioxan, etc., or mixture thereof.
The present reaction proceeds more smoothly in the presence of base such as pyridine~ picoline, quinoline, isoquino-line, triethylamine, tributylamine, ~-methylpiperidine, ~-methylmorpholine, N,N-dimethylaniline, N 9 N-diethylaniline, etc. The reaction may proceed under room temperature and is accelerated by heating. Therefore, i-t is convenient to heat at about boiling poin-t of the solven-t employed.
When a suitable conditions is selec-ted in the present reaction, an intermediate iOe. 4-bromomethylthiazole may be obtained in some casesO
Thus ob-tained compounds (XVIII) are subjected to addition reaction of hydrogen cyanide to give so-called cyanhydrin compounds For this purpose, cyanides such as sodium cyanide, potassium cyanide, e~c are generally reacted wi-th the compounds (X~III). The cyanhydrin com-pounds can be isolated as stable acyl deriva-tives by protecting with a suitable protec-tive group e.g. fcrmyl, ace-tyl, etc. ~xample of the desirable procedure is to react acetic anhydride with the cyanhydrin compounds in pyridine. ~he reaction to obtain the cycmhydrin compounds or their derivatives is preferably conducted in the solvent in the presence of baseO The solvent is desired to dissolve ~2:~ZI~
bo-th of the starting compounds and base, and water or a mixture of water and organic solvent miscible with wa-ter (e.g. me-thanol~ e-thanJl, acetone, dime-thylfo:rmamide, etc.) are generally employed. As the base emplo~edj there ma~
be conveniently used, for e~ample, such weak base as pot~s--sium dihydrogen phosphate, sodium hydrogen sulfite, triethyl-amine, etc. ~he reaction is carried out advantageously under cooling or at the neighborhood of room temperature to avoid undesirable side reaction. The reaction to obtain the cyanhydrin compounds as ~-acetoxy-acetoni-trile deriva-tives is usually conducted by reacting acetic anhydride with the fGrmer compounds in the solvent under the presence of base. ln this reaction, any of solven-t so far as it does not disturb the reaction may be employed and there may be generally used, for example, aprotic solvent such as chloroform, carbon tetrachloride, tetrahydrofuran, pyridine, dimethylformamide~ etc~, or mi~ture thereof.
Any base so far as it does no-t disturb -the present reaction can be employed and preferable ones are organic ter-tiary base such as pyric~ine, quinoline~ isoquinoline, triethyl--amine, N,N-dimethylaniline, etc Among -them, pyridine is most preferable becallse it also works as solvent Acetic anhydride mentioned ~bove is most prererable as the acylating agen-t~ bu-t other acylating agent including acetyl chloride may be also employed. The reaction proceeds smoothly under cooling~ but, if desired, it may be conducted in the neigh-borhood of room tempera-ture ~hus obtained cyanhydrin compounds containing their ;Z8~
acyl deriva-tives are subjected -to hydrolysis to give the contempla-ted compounds (XIX'), The hydrolysis is carried out in the solvent under the presence of acid or base. ~s the solvent~ methanol or ethanol are generally used, ~he reaction is conducted advantageously under cooling -to in the neighborhood of room temperature to avoid the undesi--rable side reaction. In the reaction, inorganic acid such as hydrochloric acid, sulfuric acid, etcO is preferably employed as acid and sodium hydroxide1 potassium hydroxide~
etc. is used as base.
While thus obtained a-hydroxyace-tic acid derivatives tXIX) is racemic mixture, it can be resolved into optical active isomers i,e. D-form and L-form by E~ se known processes, for example, by in-troducing them into a suitable diasteromer.
The following are some examples of the preferable ones of -the cephem compounds tI) of the presen-t in~ention.
7~--(a-Hydroxy-a-(2-aminothiaæol--4-yl)ace-tamido)-3-(1~2,3-triazol--5-ylthiom~thyl~-3 cephem-~-carbo~ylic acid 7,B-t(2-Aminothiazol~-yl)glycylc~nido)-~ -me-thyl~ tetra-zol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 7,~-((2-~minothiazol-l~-yl)~lycylamido)-Z-(1,2,3-triazol-~-ylthiomethyl)-3-cephem--L~--carboxylic acid 7a-Methoxy-7~-((2-aminothiazol-4-yl)glycylamido)cephalos-poranic acid 7a-Metho~y-7,B-((2-aminothiazol-4-yl)glycylamido)desace-toxy-cephalosporanic acid 7~-[(2-Aminothiazol-4-yl)glycylamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiome-thyl)-3~cephem-4-carboxylic acid 7~-[~-Hydroxy-(2-aminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem~4-carboxylic acid~
An embodiment of the present invention relates to a cephalosporin compound of the formula:
O ~ ~
or a pharmaceutically acceptable salt or ester thereof. A
process for producing this cephalosporin compound or its salt or ester comprises reacting an acid of the formula H N - ~ ~
N
wherein the amino group is optionally protected or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula ~Zl~
H2N ~ ~ N -N
~ N ~ ~ CH2-S N ~N
O l l or a salt or ester thereof, and if desired, converting the acid of formula (XXIV) into a pharmaceutically acceptable salt or ester thereof.
Another embodiment of the present invention relates to a cephalosporin compound of the formula:
N ~ C CONH
- ~ ~ CH2-O-C-CH3 (XXV) 3 CO2~1 or a pharmaceutically acceptable salt or ester thereof. A
process or producing this cephalosporin compound or its salt or ester comprises reacting an acid of the formula H2N--~ ~
N
- 23a -28~
wherein the amino group is optionally pro-tected, or a reactive derivative thereof, with 7-aminocephalosporanic acid or a salt or ester thereof, and if desired, convertin~ the acid o~ ~ormula (XXV) into a pharmaceutically acceptable salt or ester thereof.
Example A solution of 237 mg. of ~ trichloroethoxy-carbonylamino)-~-~2-(~ -trichloroethoxycarbonylamino)-thiazol-4-yl)acetic acid and 8 mQ. of thiony' chloride is stirred at room temperature for 1.5 hours. The excess thionyl chloride is removed under reduced pressure. To the residue are added 183 mg. of 7-aminocephalosporanic acid and 5 mQ.N,N-dimethylacetamide. The mixture is stirred for 4 hours and then 50 mQ. of ethyl ace-tate and saturated aq. NaCQ solution are added. The ethylacetate layer is separated and dried over magnesium sulfate, followed by the filtration. The filtrate is concentrated under reduced pressure to give 340 mg. of an oily residue. The residue is dissolved in excess 5~ sodium hydrogen carbonate aq. solution and subjected to column chromatography on polystyrene resin (Registered trade mark, Amberlite XAD-2; manufactured by Rohm & Haas Co., U.S.A.), followed by elution with water. The combined eluate is concentrated to obtain sodium 7~-{~ -trichloroethoxy-carbonylamino)-~-[2-~ -trichloroethoxycarbonylamino)thiazol-4~yl]-acetamido} cephalosporanate.
AnalySiS. -Calcd. for C2lHlgNsolos2cQ6Na i/2H2O
C, 31.12; H, 2.48, Found: C, 30.96; H, 2.19.
- 23b -.~ ... ..
z~
NMR (ppm, lOOMHz~ C~3C02D): 2,25(3H,s,CH3C0), 3.70(2H,q, 2-CH2), 5000(2H,s,CR3CCH2), 8,12(1H,s,-thiazole ring proton), ExamEle 2 ~o a solution of 590 mg, of 7~ -ethoxyimino-~-(2~ -trichloroethoxycarbonylamino)thiazol-4-yl)aceta-mido~ cephalosporanic acid in 30 m~Oof 90 /0 aq. formic acid is gradually added 654 mg. of zinc dus-t under stirring at 0C and the mixture is stirred for 1.5 hours at 0C.
~he insoluble materials are filtered off and washed with 50 % aq, formic acid. ~he filtrate and washings are con-centrated under reduced pressure, The residue is dissolved in 20 m~,of wa-ter and hydrogen sulfide gas is bubbled through the solution for 20 minutes and insoluble material is filtered off~ The filtrate is lyophilized to afford 380 mg, of the crude product, which is di~solved in 5 O/G`
sodium hydrogen carbonate aq, solution and purified with a column packed with ~mberlite XA~-2 ~manu~ac-tured by ~ohm & EIaas Co,,U,~,A.) to obtain sodi~ 7~-(2-aminothiazol-4-ylglycylamido)cephalosporanate.
Analysis - Calcd. for Cl5Hl6~so6s2 3 2 C, 35,7~; H, 4,40; N~ 13.90, Found C, 35,22; H, 4,03;
N7 13,7~, N~R (ppm, 100 MHz, D20): 2,25(3EI,s7CH3C0), 3.66(2H,q,2-CH2),
~0 ~lternatively, the earboxyl group may be a biologically active ester derivative, said ester derivatives being conducive to, for instance, an increased blood level or/and a longer duration of activity. As the ester residues of use for this purpose, there may be mentioned, for example, alkoxymethyl and ~-alkoxyethyl , ~6Z84 and other ~-alkoxy-~-substituted methyl ~roups, e.g. methoxy-methyl, ethoxymethyl, isopropoxymethyl, ~-methoxyethyl, ~-ethoxyethyl, e-tc.; alkylthiomethyl groups, e.g. methylthio-methyl, ethylthiomethyl, isopropylthiome-thyl, etc.; and acyloxymethyl and ~-acyloxy-~-substituted methyl groups, e.g.
pivaloyloxymethyl, ~-acetoxybutyl, etc.
Thus, the preferable examples of the present cephem compounds (I) may be the compounds that the group Rl means methyl, acetoxymethyl, (l-methyl-tetrazol-5-yl)thiomethyl, (1,2,3-triazol-5-yl)thiomethyl, (2-methyl-1,3,4-thiadiazol-5-yl)~hiomethyl, etc. These compounds (I) are all novel and useful as antibiotics. Like the known cephalosporins or penicillins, the contemplated compounds (I) of this invention can each be administered in the forms of injection, capsules, tablets, granules, solutions, suspensions, solid forms, if necessary, with a physiologically acceptable carrier or excipient in accordance with the established pharmaceutical procedure. The contemplated compounds of this invention, such as sodium 7~-methoxy-7~-(2-aminothiazol-4-ylglycylamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid may be injected intramuscularly at a daily dose level of about 5 to 20 mg./kg. human body weight in 3 to 4 divided dose per day and are effective against respiratory-organ infections, : ~`
~6~8~
urinary-trac-t infec-tions, etc. And, the compounds (I) show strong antibiotic properties against a wide variety of microorganisms including gram-positive or negative bacteria, even by oral administration.
A process for producing the compound of formula (XXI-a) or a pharmaceutically acceptable salt or ester thereof, comprises:
(1) reacting a compound of the formula:
H2N ¦ ~ ~ (VI-a) O~ -N ~ CH2 COOH
wherein R4 is as defined above, or a salt or ester of the compound (VI-a), with a compound of the formula:
N C-COOH (V-a) N
wherein Rl and R5 are as defined above, or a reactive derivative of the acid (V-a), and where necessary, removing the amino-protecting group which may be present in the radical Rl of the obtained product to give a compound of formula (XXI-a) wherein R is an amino group, or (2) reacting a compound of the formula:
~Z~6ZI~
R
N ~ C-CONH - ~ ~ S (IX-a) N O N ~ c~2 R COOH
wherein R6 represents an acyloxy or carbamoyloxy group or a halogen atom, and R and R are as defined above, or a salt or ester of the compound (IX-a), with a tertiary amine or a compound of the formula: R '-H wherein R ' represents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, and where required, removing the amino-protecting group which may be present in the radical Rl in the obtained compound to give a compound of formula (XXI-a) wherein R is an amino group, and if desired, converting any free carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into a pharmaceutically acceptable salt or ester thereof, or converting any salt or ester of the carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into the free acid or into a pharmaceutically acceptable salt or ester thereof.
Preferred condi-tions of the reactions for producing cephem compounds (I)(including compounds ~XXI) and (XXI-a) where applicable)of the present invention are described below.
(a) Reaction o~ compounds (V)(or (V-a))and (VI)(or (VI-a~).
~, , 1 1 --,~ .
~l6~
The carboxyl group of the starting compounds (VI) of this reaction may be used as a salt form with alkali me-tals, organic amines such as sodium, potassium, triethylamine, etc., or as an ester form which can be easily converted into free carboxyl group by mild treatment with an acid or alkali, or by reduction, the ester being exemplified by e.g. wi-th ~-methyl-sulfonylethyl, trimethylsilyl, dimethylsilenyl, benzhydryl, ~ trichloroethyl, phenacyl, p-methoxybenzyl, p-nitrobenzyl, methoxymethyl, etc. As the reactive derivatives of the other starting compounds (V), there may be employed acid halide, acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide, ester, etc., thereof.
This reaction can be conducted advanta~eously and smoothly in the presence of a solvent. As said solvent, use may be made of the common solvents and their mixtures unless such solvents do not interfere with the present reaction. There may be mentioned, therefore, such solvents as water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloro-methane, dichloroethylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc- This reaction may proceed more advantageously when in the solvent there is added a base such as pyridine, triethylamine, N,N-dimethylaniline, sodium hydrogen carbonate, etc.
- lla -~``/ . , ~Z~28~
The quantity of the base to be added is 100-~00 ~, desirably 100-c'OO /0 of that of the starting compounds (V). While the reaction temperature is virtually optional~ the reaction usu~lly is carried out under cooling or at room tempera-ture The reaction is generally completed within sever~l minutes to several hours.
If necessary, thus obtained compounds are subjec-ted to removal of the proteetive group and/or conversion of the convertible group~ The removal of the proteetive group of amino group may be conducted, for example, by acid trea-tment for t-buto~-ycarbonyl, ete., by a trea-tment with zine and an acid for P,'-', J ~-triehloroethoxycarbonyl~ e-tcO by catalytie reduction for p--nitrobenzyloxycarbonyl, etc The protective groups of hydroxyl group are removed, for example, by potas-sium hydrogen carbonate in aqueous methanol for formyl or trifluoroacetyl, etc., by diluted hydrochloric aeid treat-ment, for tetrahydropyrclnyl~ etc., by zine and an aeid treat-men-t for ~"'"~-triehloroethoxyearbonyl, e-tc The es-ter residues of the earboxylie aeids are removed, for ex~mple, by aeid treatment :~`OI` ben~hyclryl, p-methoxybenzyl, etc., by alkali treatment for ~-methylsulfonylethyl, ete., by aqueous treat~ent for trimethylsilyl, dimethylsilenyl, etc., by zinc-an aeid tre~tment for ~ -trichloroethyl eteO, by redue-tion for p-nitrobenzyl, ete The methylthio or methyl-seleno group e-tc. may be eonverted into methoxy group by e.g~ reacting methanol iIl the presence of metal compounds including silver, mercury, leaci, thallium, etc. The removal of the protective ~roups or the conversion of the groups 8~
may be performed at the same time if possible, or any of them may be removed or converted in accordance with -the sort of the groups and/or the reaction condition of the next step.
While the starting carboxylic acids (V) may occur as D- and L-isomers with respect to the ~-carbon, whichever of these isomers, as well as their mixture, can be successfully employed for the purposes of this invention. It is known that generally, of cephalosporins or penicillins having a center of asymmetry at ~-position, D-isomers are more antibiotic than the L-isomers.
The compounds (V) employed as the starting materials in this reaction may be prepared by the processes which will be mentioned just below and are used in that condition obtained by these processes or after removal of the protecting groups and/or conversion of the groups.
A compound of the formula:
~ (XI) N CHCOOH
(wherein the symbols have the same meanings as defined above), which is within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reducing a compound of the formula:
~2~ Z~3~
Rl R8 B ~ (IV) N CCOOH
NR
(wherein R5 represents hydroxyl group which may be protected and each of other symbols has the same meaning as defined above), or a salt or ester thereof, followed by, if necessary, removal of the protective group.
A compound o~ the formula:
~ (XIV) N C-COOH
Y Z
(wherein R represents amino or hydroxyl which may be protected and other symbols have the same meanings as defined below), which is also within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting a compound of the formula:
XCH2 - C - C - COOH (XII) Il /\
O Y Z
(wherein X means a halogen and, when Y is hydrogen, Z means amino group which may be protected or Y and Z together represent a group of the formula:
=NR5 (R5 is hydroxyl group which may be protected)), or a salt or ester thereof, and a compound of the formula:
-- 1~ --2~3~
R - C - NH2 (XIII) (wherein R13 represents a lower alkoxy group or amino group which may be protected), followed by, if necessary, removal of the protective group.
A compound of the formula:
HO ~ S
N ~ C-COOH (XVI) NR
(wherein the symbol has the same meaning as defined above) which is also within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting a compound of the formula:
H2N b,~L
N C-COOH (XV) NR
(wherein the symbol has the same meaning as defined above), or a salt or ester thereof, with a diazotizing reagent.
A compound of the formula:
1~
R ~ ~ (XIX) N CH-COOH
OH
~2~284 (wherein the symbol has the same meaning as defined below) which is within the scope of the compound of formula (V), or a salt or ester thereof, may be prepared by reacting A compound of the formula: S
R - C - NH2 (XVII) (wherein R14 represents amino group which may be protected), with trihalogenoacetone in the presence of a base to obtain a compound of the formula:
(XVIII) N CHO
(wherein the symbol has the same meaning as defined above), subjecting the compound (~VIII) to addition reaction of hydrogen cyanide and hydrolyzing thus obtained product, followed by, if necessary, removal of the protective group.
(b) Reduction of the compounds (VII) In the starting compounds (VII), the symbols other than R5 have the same meanings as defined above, and symbol R5 means hydroxyl group which may be protected. As the protect-ive groups of hydroxyl group, any oE the conventional ones may be used so far as they do not disturb the reactions of this invention and there may be generally employed a lower alkyl group such as methyl, ethyl, etc., an aryl group such as phenyl, thienylr etc., an acyl group such as acetyl, benzoyl, etc.
The reduction condition employed in the present reaction may be selected from the known reduction methods so ~ ~ - 16 -,.
~Z;3 ~84 far as the compounds tVII) can be reduced into the compounds (VIII), namely the compounds (I) wherein -A- represents -CH- , N~12 and preferable ones are the catalytic reduction employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., reduction means employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam, etc. and water, alcohols, etc. reduction means employ-ing metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, etc., reduction means treating with metals such as zinc, iron, etc. in solvents such as acetic anhydride, formic acid, or aqueous mixture thereof, etc., electroreduction, etc.
The reaction conditions such as reaction temperature, pressure, sort of the solvents, reaction time, and others are selected suitably according to the sort of starting materials, reduction means, etc. After the reduction reaction, the reaction mixture may be, if necessary, subiected to removal reaction o-f the protective group directly or after separation of the objective compounds (VIII). The removal of the protective group is conducted in accordance with the conventional removing methods employed for the removal of each protective group.
(c) Reaction of the compounds (IX) or (IX-a) with a nucleo-philic compound~
- 16a -~16;2~
In the compounds tIX), the symb~l R6 represents carbamoyloxy, an acyloxy such as acetyloxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyloxy, 2-carboxybenzoyloxy, 4-carboxybutyryloxy, mandelyloxy, 2-(carboethoxycarbamoyl)-benzoyloxy, 2-(carboethoxysulfamoyl)benzoyloxy, 3-ethoxy-carbamoylpropionyloxy, etc., a halogen such as bromine, chlorine, etc. and among them the acyloxy groups are generally employed.
The nucleophilic compounds correspond to the compounds having the symbol R of the compounds (I) mentioned above, except for hydrogen, carbamoyloxy, acyloxy and tertiary ammonium. Among the nucleophilic compounds, the mercapto compounds are reacted each in such forms as the free compound or a salt with an alkali metal such as sodium, potassium or the like. This reaction is desirably conducted in a solvent. For example, use can be made of water, heavy water or organic solvents readily miscible with water and inert to the starting compounds, such as dimethylformamide, dime-thylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfoxide, tetrahydrofuran, etc.
The reaction temperature and time depend, among other factors, upon the starting compounds, solvent, etc. to be employed but ~enerally the reaction is carried out at a selected temperature within the ran~e of 0 to 100C for a selected time of a few hours to several days. The reaction is desirably conducted in the neighborhood of neutrality or between pH 2 and 8 and, for better results, between pH 5 and 8. The reaction often proceeds more smoothly by the addition of a quaternary ammonium salt - 16b -` . `
6~34 having surface active effect (e.g. -trimethylbenzylammonium bromide, triethylbenzylammonium bromide, -triethylbenzylammonium hydroxide, etc.) to the reaction system. To prevent oxidation of the mercapto compounds, it is advantageous to carry out the reaction in an inert gaseous atmosphere, e.g. nitrogen gas.
The cephem compounds (I) obtained by the processes illustrated hereinbefore, can be purified by such procedures as column chromatography, extraction, precipitation, recrystall-ization, etc. The compounds (I), if desired, are further converted to contemplated salt or ester, etc. by a per se known process.
When A represents a group of the formula: ~C=NR , the compound (IX) may be represented by the formula:
R \ f S ~ ,R3 N ll C-CONH ~ S ~ (XX) NR5 ~ N ~ CH2R
COOH
which may be reacted with nucleophilic compounds under similar conditions mentioned above.
Each starting compound employed in the above mentioned processes for preparing the cephem compounds (I) can be prepared for example by the following processes.
(d) Reduction of the compounds (IV) Similar reduction conditions as mentioned in above - 16c -~Z~Z8~
(b) are employed in this reaction. Thè~carboxyl group of the starting compounds (IV) may be protected with a protective group removable under mild conditions which will not interfere with the thiazole ring, for example by acid or ; - 16d -~Z~L~28~
alkaline condi-tiOn reduction etc Therefore, such pro-tec-tive groups may-be selected from those of carbo~yl group generally employed in the peptide synthesis and are exempli-fied by alkali metals such as sodium, potassium, e-tc alkyl such as me-thyl~ ethyl, propyl, isopropyl, butyl, sec-butyl, isobu-tyl, tert-butyl, etc., substituted alkyl such as ~-methylsulfonylethyl, trichloroethyl 7 diphenyl-methyl, etc , aryl such as phenyl, tolyl, etcO, substituted aryl such as p--tert-butylphenyl, p-ni-trophenyl, etc., aralkyl such as benzyl, phenethyl, tolubenzyl~ etc., substituted aralkyl such as p-me-thoxybenæyl~ p-ni-trobenzyl, e-tc. In the present reaction, it seems that the starting compound ~IV) wherein ~5 is protected hydroxyl~ gives better result. The contemplated compounds ~V) may be purified by a per se known purification method such as solvent extraction, pH adjustment, crystalliæation, recrystallization, distillation, chromatography, ion-exchange chromatography, etc. The isolated compound ~) is ~L-mi~ture and may be resolved into D-foxm and ~-form respectively by introducing it to suitable op-tical-ac-tive-crystal-formin~ salt, e g.salt wi-th tartaric acid, mandelic acid, malic acid, camphor-sul~onic acid, etc.
(e) ~eaction of the compounds (XII) wi-th (~
In the starting compounds (XII), the symbol X means halogen such as chlorine, bromine, iodine~ fluorine, etc.
When Y represents hydrogen~ Z means amino group which may be protec-ted, such ~roup being exemplified above ~lter-natively, Y and Z toge-ther represent a group of the formula;
~L6284 =N~-, such group bein~ also illu~trated above, The carboxyl ~roup of the compounds (XII) may be protected in a similar manner to that mentioned in respect of the cGmpounds (:[V). In the present reaction~ it is desirflble to reac-t substantially equivalent mole of both the starting com,ounds (XII) and (XIII)o The reaction is generall~J
conducted in the solvent and such solvent may be selected from the organic solvent which ~Jill not disturb the contemp-lated reaction. Thus, methanol, ethanol, propanol 7 tetra-hydrofuran, for example~ are suitably employe~ The reac-tion is carried out smoothly at room temperature or under reflux condition. The reaction is generally comple-ted within one to several hoursO The reaction may ~e carried out more smoothly by adding base such as dimethylaniline triethylamine1 etc, to the reaction systemO ~fter the reaction i~ completed~ the removal of the protecting g:roup may be conducted directly to the reaction mixture or after isolation of the compoullds (XIV), if desired, The purification of the compounds tXI~') may be carried out by the similar means as mentioned above (d)o When the starting compounds ~III) wherein R13 represents a lower alko~y ~roup are employed~ there is obtained a contemplated compound (~IV) wherein Rl is hydroxyl according to the present reaction, (f) Dia~otization of -the compounds (XV) The carboxylic ~roup o~ the starting compounds (XV) employed in this reaction may be protected by the similar manner as mentioned in the above compounds (IV). The ~6~84 reaction is generally conducted in a solvent, for example, water or a mixture of wa-ter and organic solven-ts which are readily rniscible with water and do not disturb the present reaction such as alcohols e,g, methanol, e-thanol, etc,~
ethers e,g, tetrahydrofuran~ dioxane, etcO As the diazo-tization reagents, nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, etc, are conveniently employed and, among them, sodium nitrite1 amyl nitrite, etc. are generally used. The reaction is generally conducted in the presence of an acid at a selected temperature within the range of O to 50C for a selected time of one to several hours, The acid employed in the reaction is exemplified by hydrochloric acid, sulfuric acid 9 phosphoric acid, formic acid, acetic acid, etc, While ~-oximino-2-substituted-thiazol-~-ylacetic acid derivatives involved in these compounds (XIV) and lX~I) may occur theoretically as syn- and anti-isomer with res-pec-t to oximino group, each of the both isomers can be used, similarly for -the present reactionO
(~) Reaction o~ the compounds (XVII) and trihcllogenoacetone The symbol R14 represents such amino group which may be protected as illustrated hereinbefore and, therefore~
the com~ounds (XVII~ are exemplified by N-(trichloroethoxy-carbonyl)thiourea, N-(t-butoxycarbonyl)thiourea, N-(benzyl-oxycarbonyl~thiourea, etc~ As the trihalogenoace-tone, there are generally used, for example, lS1,3-trichloro-acetone, l,l,~-tribromoacetone, etc.
The reaction may be carried ou-t advantageously in 3l6;2~
the solvent. ~ny solvent which can dissolve both s-tarting materials may be employed so far as it does not dis-turb the reaction, and more preferably one is exemplified by alcohols such as methanol, e-thanoll propanol, etc , ke-tones such as acetone, methyl ethyl ~etone, etcO, ethers such as ether, tetrahydrofuran, dioxan, etc., or mixture thereof.
The present reaction proceeds more smoothly in the presence of base such as pyridine~ picoline, quinoline, isoquino-line, triethylamine, tributylamine, ~-methylpiperidine, ~-methylmorpholine, N,N-dimethylaniline, N 9 N-diethylaniline, etc. The reaction may proceed under room temperature and is accelerated by heating. Therefore, i-t is convenient to heat at about boiling poin-t of the solven-t employed.
When a suitable conditions is selec-ted in the present reaction, an intermediate iOe. 4-bromomethylthiazole may be obtained in some casesO
Thus ob-tained compounds (XVIII) are subjected to addition reaction of hydrogen cyanide to give so-called cyanhydrin compounds For this purpose, cyanides such as sodium cyanide, potassium cyanide, e~c are generally reacted wi-th the compounds (X~III). The cyanhydrin com-pounds can be isolated as stable acyl deriva-tives by protecting with a suitable protec-tive group e.g. fcrmyl, ace-tyl, etc. ~xample of the desirable procedure is to react acetic anhydride with the cyanhydrin compounds in pyridine. ~he reaction to obtain the cycmhydrin compounds or their derivatives is preferably conducted in the solvent in the presence of baseO The solvent is desired to dissolve ~2:~ZI~
bo-th of the starting compounds and base, and water or a mixture of water and organic solvent miscible with wa-ter (e.g. me-thanol~ e-thanJl, acetone, dime-thylfo:rmamide, etc.) are generally employed. As the base emplo~edj there ma~
be conveniently used, for e~ample, such weak base as pot~s--sium dihydrogen phosphate, sodium hydrogen sulfite, triethyl-amine, etc. ~he reaction is carried out advantageously under cooling or at the neighborhood of room temperature to avoid undesirable side reaction. The reaction to obtain the cyanhydrin compounds as ~-acetoxy-acetoni-trile deriva-tives is usually conducted by reacting acetic anhydride with the fGrmer compounds in the solvent under the presence of base. ln this reaction, any of solven-t so far as it does not disturb the reaction may be employed and there may be generally used, for example, aprotic solvent such as chloroform, carbon tetrachloride, tetrahydrofuran, pyridine, dimethylformamide~ etc~, or mi~ture thereof.
Any base so far as it does no-t disturb -the present reaction can be employed and preferable ones are organic ter-tiary base such as pyric~ine, quinoline~ isoquinoline, triethyl--amine, N,N-dimethylaniline, etc Among -them, pyridine is most preferable becallse it also works as solvent Acetic anhydride mentioned ~bove is most prererable as the acylating agen-t~ bu-t other acylating agent including acetyl chloride may be also employed. The reaction proceeds smoothly under cooling~ but, if desired, it may be conducted in the neigh-borhood of room tempera-ture ~hus obtained cyanhydrin compounds containing their ;Z8~
acyl deriva-tives are subjected -to hydrolysis to give the contempla-ted compounds (XIX'), The hydrolysis is carried out in the solvent under the presence of acid or base. ~s the solvent~ methanol or ethanol are generally used, ~he reaction is conducted advantageously under cooling -to in the neighborhood of room temperature to avoid the undesi--rable side reaction. In the reaction, inorganic acid such as hydrochloric acid, sulfuric acid, etcO is preferably employed as acid and sodium hydroxide1 potassium hydroxide~
etc. is used as base.
While thus obtained a-hydroxyace-tic acid derivatives tXIX) is racemic mixture, it can be resolved into optical active isomers i,e. D-form and L-form by E~ se known processes, for example, by in-troducing them into a suitable diasteromer.
The following are some examples of the preferable ones of -the cephem compounds tI) of the presen-t in~ention.
7~--(a-Hydroxy-a-(2-aminothiaæol--4-yl)ace-tamido)-3-(1~2,3-triazol--5-ylthiom~thyl~-3 cephem-~-carbo~ylic acid 7,B-t(2-Aminothiazol~-yl)glycylc~nido)-~ -me-thyl~ tetra-zol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 7,~-((2-~minothiazol-l~-yl)~lycylamido)-Z-(1,2,3-triazol-~-ylthiomethyl)-3-cephem--L~--carboxylic acid 7a-Methoxy-7~-((2-aminothiazol-4-yl)glycylamido)cephalos-poranic acid 7a-Metho~y-7,B-((2-aminothiazol-4-yl)glycylamido)desace-toxy-cephalosporanic acid 7~-[(2-Aminothiazol-4-yl)glycylamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiome-thyl)-3~cephem-4-carboxylic acid 7~-[~-Hydroxy-(2-aminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem~4-carboxylic acid~
An embodiment of the present invention relates to a cephalosporin compound of the formula:
O ~ ~
or a pharmaceutically acceptable salt or ester thereof. A
process for producing this cephalosporin compound or its salt or ester comprises reacting an acid of the formula H N - ~ ~
N
wherein the amino group is optionally protected or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula ~Zl~
H2N ~ ~ N -N
~ N ~ ~ CH2-S N ~N
O l l or a salt or ester thereof, and if desired, converting the acid of formula (XXIV) into a pharmaceutically acceptable salt or ester thereof.
Another embodiment of the present invention relates to a cephalosporin compound of the formula:
N ~ C CONH
- ~ ~ CH2-O-C-CH3 (XXV) 3 CO2~1 or a pharmaceutically acceptable salt or ester thereof. A
process or producing this cephalosporin compound or its salt or ester comprises reacting an acid of the formula H2N--~ ~
N
- 23a -28~
wherein the amino group is optionally pro-tected, or a reactive derivative thereof, with 7-aminocephalosporanic acid or a salt or ester thereof, and if desired, convertin~ the acid o~ ~ormula (XXV) into a pharmaceutically acceptable salt or ester thereof.
Example A solution of 237 mg. of ~ trichloroethoxy-carbonylamino)-~-~2-(~ -trichloroethoxycarbonylamino)-thiazol-4-yl)acetic acid and 8 mQ. of thiony' chloride is stirred at room temperature for 1.5 hours. The excess thionyl chloride is removed under reduced pressure. To the residue are added 183 mg. of 7-aminocephalosporanic acid and 5 mQ.N,N-dimethylacetamide. The mixture is stirred for 4 hours and then 50 mQ. of ethyl ace-tate and saturated aq. NaCQ solution are added. The ethylacetate layer is separated and dried over magnesium sulfate, followed by the filtration. The filtrate is concentrated under reduced pressure to give 340 mg. of an oily residue. The residue is dissolved in excess 5~ sodium hydrogen carbonate aq. solution and subjected to column chromatography on polystyrene resin (Registered trade mark, Amberlite XAD-2; manufactured by Rohm & Haas Co., U.S.A.), followed by elution with water. The combined eluate is concentrated to obtain sodium 7~-{~ -trichloroethoxy-carbonylamino)-~-[2-~ -trichloroethoxycarbonylamino)thiazol-4~yl]-acetamido} cephalosporanate.
AnalySiS. -Calcd. for C2lHlgNsolos2cQ6Na i/2H2O
C, 31.12; H, 2.48, Found: C, 30.96; H, 2.19.
- 23b -.~ ... ..
z~
NMR (ppm, lOOMHz~ C~3C02D): 2,25(3H,s,CH3C0), 3.70(2H,q, 2-CH2), 5000(2H,s,CR3CCH2), 8,12(1H,s,-thiazole ring proton), ExamEle 2 ~o a solution of 590 mg, of 7~ -ethoxyimino-~-(2~ -trichloroethoxycarbonylamino)thiazol-4-yl)aceta-mido~ cephalosporanic acid in 30 m~Oof 90 /0 aq. formic acid is gradually added 654 mg. of zinc dus-t under stirring at 0C and the mixture is stirred for 1.5 hours at 0C.
~he insoluble materials are filtered off and washed with 50 % aq, formic acid. ~he filtrate and washings are con-centrated under reduced pressure, The residue is dissolved in 20 m~,of wa-ter and hydrogen sulfide gas is bubbled through the solution for 20 minutes and insoluble material is filtered off~ The filtrate is lyophilized to afford 380 mg, of the crude product, which is di~solved in 5 O/G`
sodium hydrogen carbonate aq, solution and purified with a column packed with ~mberlite XA~-2 ~manu~ac-tured by ~ohm & EIaas Co,,U,~,A.) to obtain sodi~ 7~-(2-aminothiazol-4-ylglycylamido)cephalosporanate.
Analysis - Calcd. for Cl5Hl6~so6s2 3 2 C, 35,7~; H, 4,40; N~ 13.90, Found C, 35,22; H, 4,03;
N7 13,7~, N~R (ppm, 100 MHz, D20): 2,25(3EI,s7CH3C0), 3.66(2H,q,2-CH2),
5~26(1~1d~6-H)~ 5030(1H,s,CH), 5.75(1H,d77-H), 6,88 (lH,s,thiazole ring proton).
A solu-tion of l.L~0 g~ of a~ trichloroethoxy carbonylamino)-c~-(2-(~ trichloroethoxycarbonylamino)-thiazol-4-yl)acetic acid and 25 m~,of -thionyl chloricle is stirrecl at room temperature for 2 hours. The excess thionyl chloride is removed under reduced pressureO To the residue are added 1.10 g.of 7-aminocephalosporanic acid and 25 m~.
of N,~L~-dimethylacetamide and -the mixture is stirred for 5 hours at room temperature. ~o the reaction mixture are added 250 m~Oof ethyl acetate and saturated aq. NaCR
solution. The ethyl acetate layer is separated, washed with water and dried over magnesium sulfate, The solvent is distilled off under reduced pressure and the oily residue is dissolved in 100 m~Oof 90 /c formic acid. ~he solution is cooled to 0C~ followed by gradual addition of 5.0 gOof zinc dust and stirring for 3 hours at 0C. ~he insoluble ma-terials are filtered off and the filtrate is concentra-ted under reduced pressure. To the residue is added ~0 m~7.o~ water ~nd hydro~en s~llfide gas is passed through the aqueous ~olution for five minutes. The resulted insoluble materials are filtered off and the filtrate is concentrated under reduced pressure. ~he residue is clissolved in 5 % sodium hydrogen carbonate acl, solution and purified with a column packed with polystyrene resin (~mberlite XAD-2; manufactured by Rohm & Haas Co,, USA) in the same manner described in ~xample 1~ to obtain sodium 7~-(2-aminothiazol~ ylglycylclmido)cephalosporanate.
A~lalysis.-Calcd. for C15H16N506S2~ 2 C, 37.11; H, 4.1~. ~ound: ~, Z,7.09, H, 3.93 ~lKZ~3~
Example L~
~ o a solution of 4O0 gOof ~-hydroxy-~ (2~ tri-chloroethoxycarbonylamino)thiazol-4-yl)acetic acid in 40 mR
of tetrahydrofuran is introduced phosgene gas for 10 minutes at 0C. ~xcess phosgene is removed by bubbling nitrogen gas at 40C. The solvent is removed under reduced pressure -to give 4 6 g.of powdered cyclic carboxyanhydride.
Then 500 mg.of 7-aminocephalosporanic acid is suspended in 18 mROof N1~-dime-thylacetamide and 690 mg.of the cyclic carboxyanhydride is added under stirring. After stirring for 1 hour, 100 mR of ethyl acetate i5 added and the ethyl acetate layer is separated, washed with water and extrac-ted with 5 O/G sodium hydrogen carbonate a~ solutionO The extract is acidified to pH 2 0 with lN-hydrochloric acid The acid solution is again extracted with ethyl acetate, and the ethyl acetate extract is washed with saturated aq. NaCR solution and dried over magnesium sulfate. r~he solvent is removed under reduced pressure -to gi~re 85L~ mg.
of an oily residue, which is dissolved in 5 % sodium hydrogeIl carbonate aq solution and purified with cl column packed with polystyrene resin (Re~istered trade mark, Amberlite X~D-2; manufactured by Rohm & Haas CoO, U~A) in the same manner described in Ex~qmple 1, to ob-tain sodium 7~- la-hydroxy-a-[2-(~ -trichloroethoxycarbonylamino)-thiazol--L~-yl]acetamido} cephalosporanate.
Analysis - Calcd. ~or C18H16N409S~CRzNa2kH20:
C, 32.22; H, 3.16; N, 8 35. ~ound: C, ~2.16; H, 3.06;
~ , 7 84.
~Z~ 841~
NMR(ppm, lOOMHz C~`3C02D): 2. 2LL (3H~s,CH3CO), 3 70(2H q, 2-CH2) 9 4.98(2H,s,C~3CCH2), 5.22(2H,q~3-CH~), 5 28 (lH,d~6-H), 5 88(1H,d,7-H), 5.72(1H,s,CH)~ 7.48(1H, s,thiazole ring proton) Example 5 To a solution of 745 mg.of 7~-l a-hydroxy-a-~2-(~, ~,~-trichloroethoxycarbonylamino)thiazol--4--yl)acetamidol ceph~losporanic acid in 30 m~Oof 90 ~0 formic acid is gradually added 800 mg of zinc dust with stirring at 0C and the mixture is stirred for 2 hours a-t 0C The insoluble materials are filtered off and washed with 10 m~Oof 50 %
formic acid. The filtrate and washings are concentrated under reduced pressure ~he residue is dissolved in 5 %
sodium hydrogen carbonate aq solution and the insoluble materials are filtered off The filtrate is purified with a column packed with polys-tyrene resin (~nberlite XAD-2;
manuf~ctured by Ro~m ~ Haas Co.,U~A) to obtain sodium 7~-(a-hydroxy--a-(2-~mino-thia~ol-4-yl)ace-tc~ido)cephcllosporana-teO
AricllySis~ c~lcd~ :Eor C15~I15NL~07~2~ 2H2 C, ~7.OL~; H, ~ 9L~ N~ 11.52. ~'ound: C1 36 70;
H, 3.66; N, 11.86.
NMR (ppm, 100 MHz, C~3CO~D): 2.24(~H s,CH~CO), 3.70(2H,q, 2-CH2), 5.23(2H,ol,3-CH2), 5.~2(1H~d~6-H), 5.85(1H,d, 7--H), 5.56(1H~s,CH) 6~92(1H,s,thiazole ring proton).
~xc~mple 6 ~o a suspension of 1017 gOof a-e-thoxyimino-a-(2-trichloroethoxycarbonylamino)thiazol-4-yl~acetic z~
acid in 2~ m~.of water is added 3 m~of lN--sodium hydroxide aq, solution. The resul-ted solu-tion is lyophili~ed -to give the sodium sal-t, To a suspension of the sodium sal-t in Z0 m~Oof benzene are added 889 mgOof oxalyl chloride and 1 drop of ~,N-dimethylacetamide and the mixture is stirred for 1 hour a-t room temperatureO The solvent is removed under reduced pressure and the residue is dissolved in 20 m~.of acetone.
The above solution of the acid chloride in acetone is dropwise added to a solution of 817 mg.of 7 aminocephalos--poranic acid and 6~0 mg~of sodium hydrogen carbonate in 50 m~Oof water and 25 m~.of acetone while stirring for ~0 minutes at 0C. The mixture is stirred for addi-tional 2 hours at room temperatureO Acetone is distilled off under reduced pressure and the aqueous layer is washed with ethyl acetate and acidified to pH 2,0 with ~-hydro--chloric acid, The product is extracted with ethyl acetate and the combined extracts are washed wi-th water and dried over anhydrous magnesium sulfate. Concentration of the e~trac-ts affords 97~ mg.of an oily residue, ~0 mg.of which is dissolved in 5 ~, sodiu~ hydrogen carbonate solution, subjected to column chromatography on polystyrene resin (Amberlite XAD-~; manufactured by Rohm & Haas Co.,U~A) and elusion is carried out with ~0 /0 aqueous ethanol.
The frac-tions containing the contemplated compound are pooled and lyophili~ed -to obtain 18L~ mgOof sodium 7~-{ ~-ethoxyimino~ 2-(~ trichloroethoxycarbonylamino)-thia~ol-4-yl)acetamidoJI cephalosporanateO
~2~6~
y C lcdo for C20rI19N59S2C 3Na H20:
C, 35.07; H, 3.09; N, 10.23~ ~ound: C, 35.24; H, 3 18;
N, 10.~3.
NMR(ppm, 100 r'~z,C~3C02D~: 1o50(3H,t,CH3CH2)~ 2025(3H,s, CH~;C()), 3 37(2H,q,2-CH2), 4.61(2H,qlCx2cH3), ~99 (2H,s!C~3CCH2), 5.2~(2H,q,3-CH2), 5.34(1H,d,6-H),
A solu-tion of l.L~0 g~ of a~ trichloroethoxy carbonylamino)-c~-(2-(~ trichloroethoxycarbonylamino)-thiazol-4-yl)acetic acid and 25 m~,of -thionyl chloricle is stirrecl at room temperature for 2 hours. The excess thionyl chloride is removed under reduced pressureO To the residue are added 1.10 g.of 7-aminocephalosporanic acid and 25 m~.
of N,~L~-dimethylacetamide and -the mixture is stirred for 5 hours at room temperature. ~o the reaction mixture are added 250 m~Oof ethyl acetate and saturated aq. NaCR
solution. The ethyl acetate layer is separated, washed with water and dried over magnesium sulfate, The solvent is distilled off under reduced pressure and the oily residue is dissolved in 100 m~Oof 90 /c formic acid. ~he solution is cooled to 0C~ followed by gradual addition of 5.0 gOof zinc dust and stirring for 3 hours at 0C. ~he insoluble ma-terials are filtered off and the filtrate is concentra-ted under reduced pressure. To the residue is added ~0 m~7.o~ water ~nd hydro~en s~llfide gas is passed through the aqueous ~olution for five minutes. The resulted insoluble materials are filtered off and the filtrate is concentrated under reduced pressure. ~he residue is clissolved in 5 % sodium hydrogen carbonate acl, solution and purified with a column packed with polystyrene resin (~mberlite XAD-2; manufactured by Rohm & Haas Co,, USA) in the same manner described in ~xample 1~ to obtain sodium 7~-(2-aminothiazol~ ylglycylclmido)cephalosporanate.
A~lalysis.-Calcd. for C15H16N506S2~ 2 C, 37.11; H, 4.1~. ~ound: ~, Z,7.09, H, 3.93 ~lKZ~3~
Example L~
~ o a solution of 4O0 gOof ~-hydroxy-~ (2~ tri-chloroethoxycarbonylamino)thiazol-4-yl)acetic acid in 40 mR
of tetrahydrofuran is introduced phosgene gas for 10 minutes at 0C. ~xcess phosgene is removed by bubbling nitrogen gas at 40C. The solvent is removed under reduced pressure -to give 4 6 g.of powdered cyclic carboxyanhydride.
Then 500 mg.of 7-aminocephalosporanic acid is suspended in 18 mROof N1~-dime-thylacetamide and 690 mg.of the cyclic carboxyanhydride is added under stirring. After stirring for 1 hour, 100 mR of ethyl acetate i5 added and the ethyl acetate layer is separated, washed with water and extrac-ted with 5 O/G sodium hydrogen carbonate a~ solutionO The extract is acidified to pH 2 0 with lN-hydrochloric acid The acid solution is again extracted with ethyl acetate, and the ethyl acetate extract is washed with saturated aq. NaCR solution and dried over magnesium sulfate. r~he solvent is removed under reduced pressure -to gi~re 85L~ mg.
of an oily residue, which is dissolved in 5 % sodium hydrogeIl carbonate aq solution and purified with cl column packed with polystyrene resin (Re~istered trade mark, Amberlite X~D-2; manufactured by Rohm & Haas CoO, U~A) in the same manner described in Ex~qmple 1, to ob-tain sodium 7~- la-hydroxy-a-[2-(~ -trichloroethoxycarbonylamino)-thiazol--L~-yl]acetamido} cephalosporanate.
Analysis - Calcd. ~or C18H16N409S~CRzNa2kH20:
C, 32.22; H, 3.16; N, 8 35. ~ound: C, ~2.16; H, 3.06;
~ , 7 84.
~Z~ 841~
NMR(ppm, lOOMHz C~`3C02D): 2. 2LL (3H~s,CH3CO), 3 70(2H q, 2-CH2) 9 4.98(2H,s,C~3CCH2), 5.22(2H,q~3-CH~), 5 28 (lH,d~6-H), 5 88(1H,d,7-H), 5.72(1H,s,CH)~ 7.48(1H, s,thiazole ring proton) Example 5 To a solution of 745 mg.of 7~-l a-hydroxy-a-~2-(~, ~,~-trichloroethoxycarbonylamino)thiazol--4--yl)acetamidol ceph~losporanic acid in 30 m~Oof 90 ~0 formic acid is gradually added 800 mg of zinc dust with stirring at 0C and the mixture is stirred for 2 hours a-t 0C The insoluble materials are filtered off and washed with 10 m~Oof 50 %
formic acid. The filtrate and washings are concentrated under reduced pressure ~he residue is dissolved in 5 %
sodium hydrogen carbonate aq solution and the insoluble materials are filtered off The filtrate is purified with a column packed with polys-tyrene resin (~nberlite XAD-2;
manuf~ctured by Ro~m ~ Haas Co.,U~A) to obtain sodium 7~-(a-hydroxy--a-(2-~mino-thia~ol-4-yl)ace-tc~ido)cephcllosporana-teO
AricllySis~ c~lcd~ :Eor C15~I15NL~07~2~ 2H2 C, ~7.OL~; H, ~ 9L~ N~ 11.52. ~'ound: C1 36 70;
H, 3.66; N, 11.86.
NMR (ppm, 100 MHz, C~3CO~D): 2.24(~H s,CH~CO), 3.70(2H,q, 2-CH2), 5.23(2H,ol,3-CH2), 5.~2(1H~d~6-H), 5.85(1H,d, 7--H), 5.56(1H~s,CH) 6~92(1H,s,thiazole ring proton).
~xc~mple 6 ~o a suspension of 1017 gOof a-e-thoxyimino-a-(2-trichloroethoxycarbonylamino)thiazol-4-yl~acetic z~
acid in 2~ m~.of water is added 3 m~of lN--sodium hydroxide aq, solution. The resul-ted solu-tion is lyophili~ed -to give the sodium sal-t, To a suspension of the sodium sal-t in Z0 m~Oof benzene are added 889 mgOof oxalyl chloride and 1 drop of ~,N-dimethylacetamide and the mixture is stirred for 1 hour a-t room temperatureO The solvent is removed under reduced pressure and the residue is dissolved in 20 m~.of acetone.
The above solution of the acid chloride in acetone is dropwise added to a solution of 817 mg.of 7 aminocephalos--poranic acid and 6~0 mg~of sodium hydrogen carbonate in 50 m~Oof water and 25 m~.of acetone while stirring for ~0 minutes at 0C. The mixture is stirred for addi-tional 2 hours at room temperatureO Acetone is distilled off under reduced pressure and the aqueous layer is washed with ethyl acetate and acidified to pH 2,0 with ~-hydro--chloric acid, The product is extracted with ethyl acetate and the combined extracts are washed wi-th water and dried over anhydrous magnesium sulfate. Concentration of the e~trac-ts affords 97~ mg.of an oily residue, ~0 mg.of which is dissolved in 5 ~, sodiu~ hydrogen carbonate solution, subjected to column chromatography on polystyrene resin (Amberlite XAD-~; manufactured by Rohm & Haas Co.,U~A) and elusion is carried out with ~0 /0 aqueous ethanol.
The frac-tions containing the contemplated compound are pooled and lyophili~ed -to obtain 18L~ mgOof sodium 7~-{ ~-ethoxyimino~ 2-(~ trichloroethoxycarbonylamino)-thia~ol-4-yl)acetamidoJI cephalosporanateO
~2~6~
y C lcdo for C20rI19N59S2C 3Na H20:
C, 35.07; H, 3.09; N, 10.23~ ~ound: C, 35.24; H, 3 18;
N, 10.~3.
NMR(ppm, 100 r'~z,C~3C02D~: 1o50(3H,t,CH3CH2)~ 2025(3H,s, CH~;C()), 3 37(2H,q,2-CH2), 4.61(2H,qlCx2cH3), ~99 (2H,s!C~3CCH2), 5.2~(2H,q,3-CH2), 5.34(1H,d,6-H),
6.06(1H,d,7-~I), 7095(1H,s,thiazole ring proton).
E~ple 7 To a suspension of 390 mg of ct-e-thoxyimino-~-(2-trichloroethoxycarbonylamino)thiazol-4-yl )acetic acid in 5 mR.of benzene are added 300 mg. of oxalylchloride and 1 drop of N,N-dime-thylformamide and the mixture is s-tirred for 2 hours at room tempera-ture. The solvent is removed under reduced pressure and -the residue is dissolved in 10 m~.of acetone. The acetone solution is dropwise added while stirring for 30 minutes to a solu-tion of 272 mg.
of 7-aminocephalosporanic acid and 252 mg~of sodium hydrogen carbon~le in 20 m~Oof water and 10 mR.of acetone ~t C)C.
The mixture is stirred for addi.-tional 2 hours at room temperature and the solvent is clistilled off under reduced pressure. The residual aqueous solution is washed with ethyl acetate ~ncl acidified to pH 2.0 with lN--hydrochloric acidO The solution is extracted with ethyl acetate and the combined extracts are washed with wa-ter and dried over anhydrous magnesium sulfate~ :Evaporation of the solven-t affords 7~3-{o~-ethoxyimino-~-(2-(~ -trichloroethoxy-carbonylamino)thiazol--4-yl )-acetamido 1 cephalosporanic acid This product is identical with the compound obtained in ~L6Z15 ~
~xample 6 in ~MR spectrurn (in CF3C02D).
~xample To a suspension of 390 mgOof a--ethoxyimino-~-(2-~ trichloroethoxycarbonylamino)thiazol-4-yl)acetic acid in 10 me~of me-thylene chloride is added wi-th stirrinæ
312 mg.of phosphorus pentachloride.
The mixture becomes homogeneous while stirring within 10 seconds. After stirring for additional one hour at room temperature, the solvent is distilled of~ under reduced pressure and the residue is dissolved in 5 m~Oof acetoneO The ace-tone solution is dropwise added for 30 minutes to a solution of 272 mg.of 7--c~minocephalosporanic acid and 840 mgOof sodium hydrogen carbonate in lU m~.of water and 5 m~,of acetone at CC, The mixture is stirred for additional 2 hours at room temperature and acetone is removed under reduced pressure. The residual aqueous solution is washe~ with ethyl aceta-te and acidi~ied to pH ~0 with lN hydroch:Loric acid, The solu-tion is extracted with ethyl acetate and the ex-tracts are washed wi-th water and dried over anhydrous magnesium sulfateO Removal of the solvent gives 7~- la-ethoxyimino-a-~2-(~ -trichloro~
ethoxycarbonylclmino)thiazlol-4--yl)acetamidol cephalosporanic acid. This product is identical wi-th the compound obtained in ~xample 6 in ~r~R spectrum (in C~3C02D)o xample _ 9 To a suspension of 347 mg.of a-oximino-a-(2-(~
trichloroethoxycarbonylamino)thiazol-4-yl(acetic acid in ~216;~8~
20 m~Oof water is added 2 m~ of lN-sodium hydroxide solu-tionO The solution is lyophilized to give -the sodium salt To a suspension of -the sodium sal-t in 10 m~Oof benzene are added 300 mg.of oxalyl chloride and 1 drop of ~,M-dime-thylace-tamide and the mixture is stir ed for 1 hour at room ternpera-ture. ~he solvent is distilled o~f unde:r reduced pressure and the residue is dissolved in 10 m~-of acetone The acetone solution is dropwise added to a solu-tion of 261 mg~of 7-amino--cèphalosporanic acid and 200 mg.
of sodium hydrogen carbonate in 1~ m~.of water under stirring at 0C in the course o:C 10 minutes. The mixture is stirred for additional 2 hours at room tempera-ture. Ace-tone is distilled off under reduced pressure and -the aqueous solu-tion is washed with ethyl acetate and acidified to pH 2 0 with lN-hydrochloric acidO ~he product is extracted with ethyl acetate and -the combined extracts are washed with water and dried over anhydrous magnesi~ sulfate Evaporation of -the solvent affords 7~- [a-oximino-a-(2-(B,B,~-trichloro~-thoxycarbonylamino)thi~zol-'~-yl)acetc~ido) -cephalosporanic ~lcid.
NM~ (ppm, 100 MHz, CDC~3+d~-~r~S0) o 2.00(~H s,CH~C0)93.46 (2H7q~2-CH2), 4.&5(2H,s,G~;CCH2), 4.96(2H,q,3-CH2), 5.~6(1H,d,6--CH), 5 ~9(1H,q,7--CH), 7 39(1H s,thiazole ring pro-ton), 9 26(1H,d,7-NH).
~xample 10 A solu-tion of 900 mg. of a-(B3~,B-trichloroethoxy-carbonylamino)-a-(2-(B,~,B--trichloroethoxycarbonyl~mino)-thiazol-4-yl)acetic acid and 15 m~.of thionyl chloride is ~Z~Z8~
stirred a-t room temperature for 1,5 hours, The excess thionyl chloride is removed un~er reduced pressureO To the oily residue are added 700 mg,of 7-aminocephalosporanic acid and 15 m~,of N,~-dimethylacetamide and the mixture is stirred for 4 hours at room temperature. The reaction mixture is added 100 m~Oof ~-thyl acetate and then is washed ~ith satura-ted aq, NaC~ solution. The ethyl aceta-te layer is separated and dried over magnesium sulfateO The solvent is remo-~ed under reduced pressure to give an oily residue, which is dissolved in 50 m~.of 90 /0 :~ormic acid, The solu-tion is cooled to 0C and 2,0 g,of zinc dust is gradually added, The mixture is stirred for 1,5 hours at 0C, The insoluble materials are filtered off and the fil-trate is concentrated under reduced pressureO To the residue is added 20 m~.of water c~nd t,hen hydro~en sulfide gas is passed through the aqueous solution, The resulted insoluble materials are filtered off and the filtrate is concentra-ted under reduced pressure, The residue is dissolved in 5 /0 sodium hydrogerl carbonate aq, solution and purified with ~ col~nn packed wi-th polystyrene resin (~mber-lite XAD-2; manufactured by ~ohm & Haas CoO1USA) in the same manner described in ~xample 1, to obtain sodium 7~-(2-aminothi~zol~4-yl~lycylamido)-cephalosporanate, This product is iden-tical with the compound obtained in Example in all respects, ~xample 11 To a suspension of 1~56~ g,of a-ethoxyimino-a-(2-(13,~,~~trichloroethoxycarbonylc~mino)thiazol-4-yl)c~cetic 8~
acid in 20 m~.of me-thylene chloride is added 10250 g of phosphorus pentachloride while stirring. The mixture is s-tirred for 1 hour a-t room temperature and concentra-ted under reduced pressure. ~he residue is dissolved in 20 m~O
of acetone. The acetone solution thus obtained is drop-wise added to a solution of 857 mg.of 7-amino desacetoxy cephalosporanic acid and 1.68 g~of sodium hydrogen carbonate in 40 m~-of water and 20 m~Oof acetone at 0C under stirring in the course of ~0 minutes. ~he mixture is stirred for 2 hours at room temperature and acetone is distilled off under reduced pressure. ~he residual aqueous solution is washed with ethyl acetate, acidified to pH 2.0 with lN-hydrochloric acid and extracted with ethyl acetate. The combined extracts are washed with water and dried over anhydrous magnesium sulfate ~vaporation of the solvent affords 2.04 g.7~ ethoxyimino-a-~2~ trichloro--ethoxycarbonylamino)thiazol 4--yl)acetamidol~desacetoxy-cephalosporanic acid. Yield 86,9 ,~.
NMR (ppm, 100 MHz, CDC~3-~d6-LMS0):
1,26(3H,t,CH CH~), 2,13(ZH,s,3-^CH3), 3.40(2H,~2-CH2)~
4 23(2H,q,CH2CH~), 4 86(2H,s,C~3CCH2), 5 06(1H,d, 6-H), 5.80(1H,q,7-H), 7 26 an~ 7 83(1H, two s, thiazole ring proton)~
573 mg.of the acid ob-tained in the above method is dissolved in 5 % sodium hydrogen carbonate aq~ solution, subjec-ted -to column chromatography on polystyrene resin~
Amberlite ~AD-2 (manufactured by Rohm & Haas Co ,USA) and eluted with 50 /c aqueous ethanol. ~he fractions containing the contemplated compound are pooled and lyophilized to obtain 233 mg.of sodium 7~3--la-ethoxyimino-~-(2-(~
trichloroethoxycarbonyl~nino)thiazol-4-yl)acetamido} des-acetoxycephalosporanate, Yield 39,2 /0.
Analysis - Calcd, for C18H17N507S2C 3 2 C, 34,49; H, 3,06; N, 11017, Found; C, 34.96; H, 3,43;
N, 11,17, ~xample 12 ~ o a solution of 1~467 g,of 7~ ethoxyimino-a-(2-(~ -trichloroethoxycarbonylamino)thiazol-4-yl)-acetamidol -desacetoxycephalosporanic acid in 80 m~Oof 90 % aq, formic acid is gradually added 1,634 g,of zinc dust at 0C and the mixture is stirred for 1.5 hours at 0C. The insoluble material is filtered off and washed with 50 ~0 aq, formic acid; The filtrate and washings are concentrated under reduced pressure and 200 m~.of water is added to the residue. Hydrogen sulfide ~as is ~bubbled through the aqueous solution and insoluble material is filtered off, The :Eiltrate is lyophilized to yield 1.15 g, of -the formate, Yield 100 yO, The formate is dissolved in 5 ~ sodium hydrogen carbonate aq. solu-tion and purified wi-th a col~n packed with Amberlite XAD-2 (manufactured by Rohm ~ Haas Co,,USA) to afford 614 mgOof sodium 7B-(2-aminothiazol-4-ylglycylamido)desacetoxycephalosporanate.
Yield 6?,7 %
Analysis - Calcd, for C13H14N504$2N k 2 C, 37.31; H, 4.10; N, 16.74. Found: C~ 37.81 H, 4.2L~; ~, 16.69.
_ 3L~ _ 8~
NMR(ppm, 100 MEz, D20): 2 05(3H,s,~-CHz)~ 3 48(2H,q,2-CH2), 5.13(1H,s,CH), 5ol8(1H,~,6-H), 5 79(1H,d,7--H), 6 99 (lH,s,tniazole ring proton).
~xample lZ
A mixture of 650 mgOof ~-ethoxyimino-~-(2-hydroxy-thiazol-4-yl)acetic acid and 750 mgOof phosphorus pen-ta-chloride in 50 m~.of dry ether is stirred for 2 hours at room tempera-ture The acid chloride solution is added to a suspension of 1 10 gOof 7--aminocephalosporanic acid in Z0 m~ of N,N--dimethylacet~li~e and the mixture is stirred for 3 5 hours at room temperature To the mixture is added 200 m~-of ethyl acetate and the organic solution is washed
E~ple 7 To a suspension of 390 mg of ct-e-thoxyimino-~-(2-trichloroethoxycarbonylamino)thiazol-4-yl )acetic acid in 5 mR.of benzene are added 300 mg. of oxalylchloride and 1 drop of N,N-dime-thylformamide and the mixture is s-tirred for 2 hours at room tempera-ture. The solvent is removed under reduced pressure and -the residue is dissolved in 10 m~.of acetone. The acetone solution is dropwise added while stirring for 30 minutes to a solu-tion of 272 mg.
of 7-aminocephalosporanic acid and 252 mg~of sodium hydrogen carbon~le in 20 m~Oof water and 10 mR.of acetone ~t C)C.
The mixture is stirred for addi.-tional 2 hours at room temperature and the solvent is clistilled off under reduced pressure. The residual aqueous solution is washed with ethyl acetate ~ncl acidified to pH 2.0 with lN--hydrochloric acidO The solution is extracted with ethyl acetate and the combined extracts are washed with wa-ter and dried over anhydrous magnesium sulfate~ :Evaporation of the solven-t affords 7~3-{o~-ethoxyimino-~-(2-(~ -trichloroethoxy-carbonylamino)thiazol--4-yl )-acetamido 1 cephalosporanic acid This product is identical with the compound obtained in ~L6Z15 ~
~xample 6 in ~MR spectrurn (in CF3C02D).
~xample To a suspension of 390 mgOof a--ethoxyimino-~-(2-~ trichloroethoxycarbonylamino)thiazol-4-yl)acetic acid in 10 me~of me-thylene chloride is added wi-th stirrinæ
312 mg.of phosphorus pentachloride.
The mixture becomes homogeneous while stirring within 10 seconds. After stirring for additional one hour at room temperature, the solvent is distilled of~ under reduced pressure and the residue is dissolved in 5 m~Oof acetoneO The ace-tone solution is dropwise added for 30 minutes to a solution of 272 mg.of 7--c~minocephalosporanic acid and 840 mgOof sodium hydrogen carbonate in lU m~.of water and 5 m~,of acetone at CC, The mixture is stirred for additional 2 hours at room temperature and acetone is removed under reduced pressure. The residual aqueous solution is washe~ with ethyl aceta-te and acidi~ied to pH ~0 with lN hydroch:Loric acid, The solu-tion is extracted with ethyl acetate and the ex-tracts are washed wi-th water and dried over anhydrous magnesium sulfateO Removal of the solvent gives 7~- la-ethoxyimino-a-~2-(~ -trichloro~
ethoxycarbonylclmino)thiazlol-4--yl)acetamidol cephalosporanic acid. This product is identical wi-th the compound obtained in ~xample 6 in ~r~R spectrum (in C~3C02D)o xample _ 9 To a suspension of 347 mg.of a-oximino-a-(2-(~
trichloroethoxycarbonylamino)thiazol-4-yl(acetic acid in ~216;~8~
20 m~Oof water is added 2 m~ of lN-sodium hydroxide solu-tionO The solution is lyophilized to give -the sodium salt To a suspension of -the sodium sal-t in 10 m~Oof benzene are added 300 mg.of oxalyl chloride and 1 drop of ~,M-dime-thylace-tamide and the mixture is stir ed for 1 hour at room ternpera-ture. ~he solvent is distilled o~f unde:r reduced pressure and the residue is dissolved in 10 m~-of acetone The acetone solution is dropwise added to a solu-tion of 261 mg~of 7-amino--cèphalosporanic acid and 200 mg.
of sodium hydrogen carbonate in 1~ m~.of water under stirring at 0C in the course o:C 10 minutes. The mixture is stirred for additional 2 hours at room tempera-ture. Ace-tone is distilled off under reduced pressure and -the aqueous solu-tion is washed with ethyl acetate and acidified to pH 2 0 with lN-hydrochloric acidO ~he product is extracted with ethyl acetate and -the combined extracts are washed with water and dried over anhydrous magnesi~ sulfate Evaporation of -the solvent affords 7~- [a-oximino-a-(2-(B,B,~-trichloro~-thoxycarbonylamino)thi~zol-'~-yl)acetc~ido) -cephalosporanic ~lcid.
NM~ (ppm, 100 MHz, CDC~3+d~-~r~S0) o 2.00(~H s,CH~C0)93.46 (2H7q~2-CH2), 4.&5(2H,s,G~;CCH2), 4.96(2H,q,3-CH2), 5.~6(1H,d,6--CH), 5 ~9(1H,q,7--CH), 7 39(1H s,thiazole ring pro-ton), 9 26(1H,d,7-NH).
~xample 10 A solu-tion of 900 mg. of a-(B3~,B-trichloroethoxy-carbonylamino)-a-(2-(B,~,B--trichloroethoxycarbonyl~mino)-thiazol-4-yl)acetic acid and 15 m~.of thionyl chloride is ~Z~Z8~
stirred a-t room temperature for 1,5 hours, The excess thionyl chloride is removed un~er reduced pressureO To the oily residue are added 700 mg,of 7-aminocephalosporanic acid and 15 m~,of N,~-dimethylacetamide and the mixture is stirred for 4 hours at room temperature. The reaction mixture is added 100 m~Oof ~-thyl acetate and then is washed ~ith satura-ted aq, NaC~ solution. The ethyl aceta-te layer is separated and dried over magnesium sulfateO The solvent is remo-~ed under reduced pressure to give an oily residue, which is dissolved in 50 m~.of 90 /0 :~ormic acid, The solu-tion is cooled to 0C and 2,0 g,of zinc dust is gradually added, The mixture is stirred for 1,5 hours at 0C, The insoluble materials are filtered off and the fil-trate is concentrated under reduced pressureO To the residue is added 20 m~.of water c~nd t,hen hydro~en sulfide gas is passed through the aqueous solution, The resulted insoluble materials are filtered off and the filtrate is concentra-ted under reduced pressure, The residue is dissolved in 5 /0 sodium hydrogerl carbonate aq, solution and purified with ~ col~nn packed wi-th polystyrene resin (~mber-lite XAD-2; manufactured by ~ohm & Haas CoO1USA) in the same manner described in ~xample 1, to obtain sodium 7~-(2-aminothi~zol~4-yl~lycylamido)-cephalosporanate, This product is iden-tical with the compound obtained in Example in all respects, ~xample 11 To a suspension of 1~56~ g,of a-ethoxyimino-a-(2-(13,~,~~trichloroethoxycarbonylc~mino)thiazol-4-yl)c~cetic 8~
acid in 20 m~.of me-thylene chloride is added 10250 g of phosphorus pentachloride while stirring. The mixture is s-tirred for 1 hour a-t room temperature and concentra-ted under reduced pressure. ~he residue is dissolved in 20 m~O
of acetone. The acetone solution thus obtained is drop-wise added to a solution of 857 mg.of 7-amino desacetoxy cephalosporanic acid and 1.68 g~of sodium hydrogen carbonate in 40 m~-of water and 20 m~Oof acetone at 0C under stirring in the course of ~0 minutes. ~he mixture is stirred for 2 hours at room temperature and acetone is distilled off under reduced pressure. ~he residual aqueous solution is washed with ethyl acetate, acidified to pH 2.0 with lN-hydrochloric acid and extracted with ethyl acetate. The combined extracts are washed with water and dried over anhydrous magnesium sulfate ~vaporation of the solvent affords 2.04 g.7~ ethoxyimino-a-~2~ trichloro--ethoxycarbonylamino)thiazol 4--yl)acetamidol~desacetoxy-cephalosporanic acid. Yield 86,9 ,~.
NMR (ppm, 100 MHz, CDC~3-~d6-LMS0):
1,26(3H,t,CH CH~), 2,13(ZH,s,3-^CH3), 3.40(2H,~2-CH2)~
4 23(2H,q,CH2CH~), 4 86(2H,s,C~3CCH2), 5 06(1H,d, 6-H), 5.80(1H,q,7-H), 7 26 an~ 7 83(1H, two s, thiazole ring proton)~
573 mg.of the acid ob-tained in the above method is dissolved in 5 % sodium hydrogen carbonate aq~ solution, subjec-ted -to column chromatography on polystyrene resin~
Amberlite ~AD-2 (manufactured by Rohm & Haas Co ,USA) and eluted with 50 /c aqueous ethanol. ~he fractions containing the contemplated compound are pooled and lyophilized to obtain 233 mg.of sodium 7~3--la-ethoxyimino-~-(2-(~
trichloroethoxycarbonyl~nino)thiazol-4-yl)acetamido} des-acetoxycephalosporanate, Yield 39,2 /0.
Analysis - Calcd, for C18H17N507S2C 3 2 C, 34,49; H, 3,06; N, 11017, Found; C, 34.96; H, 3,43;
N, 11,17, ~xample 12 ~ o a solution of 1~467 g,of 7~ ethoxyimino-a-(2-(~ -trichloroethoxycarbonylamino)thiazol-4-yl)-acetamidol -desacetoxycephalosporanic acid in 80 m~Oof 90 % aq, formic acid is gradually added 1,634 g,of zinc dust at 0C and the mixture is stirred for 1.5 hours at 0C. The insoluble material is filtered off and washed with 50 ~0 aq, formic acid; The filtrate and washings are concentrated under reduced pressure and 200 m~.of water is added to the residue. Hydrogen sulfide ~as is ~bubbled through the aqueous solution and insoluble material is filtered off, The :Eiltrate is lyophilized to yield 1.15 g, of -the formate, Yield 100 yO, The formate is dissolved in 5 ~ sodium hydrogen carbonate aq. solu-tion and purified wi-th a col~n packed with Amberlite XAD-2 (manufactured by Rohm ~ Haas Co,,USA) to afford 614 mgOof sodium 7B-(2-aminothiazol-4-ylglycylamido)desacetoxycephalosporanate.
Yield 6?,7 %
Analysis - Calcd, for C13H14N504$2N k 2 C, 37.31; H, 4.10; N, 16.74. Found: C~ 37.81 H, 4.2L~; ~, 16.69.
_ 3L~ _ 8~
NMR(ppm, 100 MEz, D20): 2 05(3H,s,~-CHz)~ 3 48(2H,q,2-CH2), 5.13(1H,s,CH), 5ol8(1H,~,6-H), 5 79(1H,d,7--H), 6 99 (lH,s,tniazole ring proton).
~xample lZ
A mixture of 650 mgOof ~-ethoxyimino-~-(2-hydroxy-thiazol-4-yl)acetic acid and 750 mgOof phosphorus pen-ta-chloride in 50 m~.of dry ether is stirred for 2 hours at room tempera-ture The acid chloride solution is added to a suspension of 1 10 gOof 7--aminocephalosporanic acid in Z0 m~ of N,N--dimethylacet~li~e and the mixture is stirred for 3 5 hours at room temperature To the mixture is added 200 m~-of ethyl acetate and the organic solution is washed
7 times with water. The ethyl ace-tate layer is ccncen-trated under reduced pressure and -the residue is dissolved in 5 %
sodi1~ hydrogen carbonate aq solution ~nd purified with a column packed with Amberli-te XA~-2 to afford sodium 7~-(~-ethoxyimino-~-(2-hydroxythiazol--4--yl)acetamido)cephalos-poranate AnalysiS - Calcd for C17~-I17N~~N 2 C, 37 ~6; H, 4 249 N, 10 250 Found: C~ 37 Z7;
H, 3 90; N, 9 8~;
NMR(ppm, 100 MHz, CFzCO2D): 1 44(ZH,t,CH~CH2), 2 21(3H,s, CH~C0) 9 ~ 70(2H,a)2-CH2), 4.48(2H,q,CH2CH3), 5 25 (2H,q,~-CH2), 5 ~0(1H,d,6-H), 6 05(1H,d97-H), 7.1Z
(lH,s,thiazole ring proton).
xc~mEle 14 To a suspension of 1 08 g of ~-ethoxyimino-~-(2-
sodi1~ hydrogen carbonate aq solution ~nd purified with a column packed with Amberli-te XA~-2 to afford sodium 7~-(~-ethoxyimino-~-(2-hydroxythiazol--4--yl)acetamido)cephalos-poranate AnalysiS - Calcd for C17~-I17N~~N 2 C, 37 ~6; H, 4 249 N, 10 250 Found: C~ 37 Z7;
H, 3 90; N, 9 8~;
NMR(ppm, 100 MHz, CFzCO2D): 1 44(ZH,t,CH~CH2), 2 21(3H,s, CH~C0) 9 ~ 70(2H,a)2-CH2), 4.48(2H,q,CH2CH3), 5 25 (2H,q,~-CH2), 5 ~0(1H,d,6-H), 6 05(1H,d97-H), 7.1Z
(lH,s,thiazole ring proton).
xc~mEle 14 To a suspension of 1 08 g of ~-ethoxyimino-~-(2-
8~
hydroxythiazol~ yl)ace-tic acid in 20 m~ of absolute ether is added 1.25 gOof phosphorus pen-tachloride and the mix-ture is stirred for 2 hours a-t room temperatureO ~he acid chloride solution is dropwise added to a suspension of 1.80 gOof 7--aminocephalosporanic acid in 50 m~Oof N,N-dimethylacet.~ide and -the mixture is stirred for ~ hours at room temperature. The mixture is e~trac-ted 3 times with each 120 m~Oof ethyl acetate and the combined eY~trac-ts are washed with water and dried over anhydrous ma~nesi~u~
sulfate. The solvent is removed and the residue is dissolved in 60 m~ of 90 /0 aq. formic acid~ To the acidic solution is added 4,~0 ~;.of zinc dust at 0C and -the mixture is s-tirred for 2 hours at this temperature.
Insoluble material is filtered off and the filtrate is concentrated under reduced pressure, To the residue is added 20 m~.of water and hydrogen sulfide gas is bubbled through the aqueous solution for 5 minutes, Insoluble material is filtered off and the fil-trate is a~ain concen-t-rclted. The residlle is dissolved i~ 5 /0 sodium hydro~en carbonate aq. solution and purified with a column packed with Amberlite XAD-2. The fractions obtained by the eluation with 5 /~ aqueous ethanol is lyophilized to afford sodium '7~-(2-hydroxythiazol-4--ylglycyl~lido)-cephalosporanate, Analysis - Calcd. for C15H15N~07S2Na H20 C, 3~.46; H, 3~66; N7 11.96. ~ound: C, 38035;
H~ 4,04j N, 12.2~o ~xample 15 A solution of 10.0 g,of N~ -trichloroe-thoxy-carbonyl)thiourea, 12.0 gOof 1,l ,3-tribromoacetone and 5,0 g, of dimethylaniline in lO0 m~.of e-thanol is heatecl under reflux for 2 hours, After cooling9 e-thanol is re~noved under reduced pressure, and the oily residue is dissolved in ethyl aceta-te. Ethyl acetate layer is washed with water and dried over MgSOL,, :E~thyl acetate is removed under reduced pressure and the oily residue is dissolved in small quantity of chloroform. ~rom the solution which is allowed to stand at room temperature is obtained 2-( trichloLoethoxycarbonyl)amirlo-4-îormylthiazole as a crystalline form, 5.0 g. Melting point: 188-190C.
Analysis - Calcd. for C7H503N~ C~3:
C, 27.69; H, 1.66; N9 9.23. ~ound. C, 27.87;
H, 1.69; N! 9.01.
NMR (ppm, lO0 MHz, Cl~C~7~,-d~, LMS0);
5.05(2H,s,C~3CCH2--), 8.05(1H,s,5-H), 9.80(1H,s,CH0) ~ o a mixture of l,0 g~ of 2-(~7~ trichloroe-thoxy-cn:rbony'l)arnirlo-4-formyl-thiazo:le, 0.~7 F~o OI KH2P0~ mk70 of water and 4 m~0 of dimethylformamide is added 0.33 g, of KCN at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of ethyl acetate ~;ives ~-hydroxy--[2~ 3-trichloroethoxycarbonyl)aminothiazol-4-yl )--acetonitrile 1,127 g, NMR (ppm, 100 MHz, CDC~73): 4,90(2H9s,C~73CCH2-), 5.70 (lH,s7--CHCN), 7.90(1H9s,5H)o ~6~84 Example 17 To a solution of 1.10 g of a-hydroxy--(2-(~
trichloroethoxycarbonyl)aminothiazol-4-yl)ace-tonitrile in 1 m~-of pyridine is added 2.5 m~ of acetic anhydride under ice-cooling and the mixture is stirred for 1 hour. ~o the mixture is added ether and water and the organic layer is washed with aq NaHC03 and further water in this order.
Evaporation of ether gives a-acetoxy-~2~ -trichloro-ethoxycarbonyl)aminothiazol-4-yl)acetonitrile. 1 ~ g.
~MR(ppm, 100 MHz, CDC~3): 2 20(3H,s,C0CH3), 5 00(2H,s, CRzCCH2-), 6 60(1H,s, `CEICN), 7.30(1H,s,5 H) Example _18 To a solution of 1.30 g of a-acetoxy-~2-(~
trichloroethoxycarbonyl)aminothiazol~4-yl)acetonitrile in 10 m~.of methanol is bubbled gaseous hydrochloric acid for 10 minutes under ice-cooling, and the mixture is kept standing at room temperature for 1 hour. After eva-poration of methanol is added 40 m~.of 50 % aq methanol to the residue and s-tirred for 1 hour To -this reaction mixture is added 1 0 g.of NaOH and s-tirrecl for 1 hourO Methanol is removed under reduced pressure and the residue is extracted with ethyl aceta-te af`-ter being made acidic wi-th N-HC~
Ethyl aceta-te layer is washed with water and dried. ~thyl aceta-te is removed under reduced pressure to obtain a-hydro-xy-(2~ -trichloroethoxycarbonyl)amino)-thiazol-4-yl acetic acid. 0 995 g. Melting point: 135-136C.
~nalysis - Calcd for C8H705N2SC~3:
C, 27 48; H 2.02; N, 8 01. Found: C, 27.72; H, 2.05;
N, 8 08.
~ 38 -L6~
NMR(ppm, 100 MHz, CDC~3): 4,90~2H,S,c~3ccH2~) t 5-~0(1II,s~
,CH -COOH), 7.10(lH,s~5-H).
~xample 19 To a solution of 21,43 gO of ethyl a-ethoxyimino~
oxo-~-bromobutyrate in ~30 m~Oof ethanol is added 8081 g of methyl-thionocarbamate and the mixture is heated under reflux for 1.5 hours, A-ter coolin~; ethanol is removed under reduced pressure and the oily residue is dissolved in chloroform. The chloroform solution is washed, dried, and condensed. The condensate is purified by silica gel chromatography to give 11.9 g, of ethyl c~-ethoxyimino-(2-hydroxythiazol--4-yl)aceta-te. Mel-tin~ point: 54-55C.
Analysis - Calcd. for CgH1204N2S:
C, 44.25; H, 4,95; ~ 7. ~ound: C, 44.54; H, 5004;
~ i, 11.5~.
NMR(ppm, 100 MHz, CDC~ 6.Z3(1H,s,5-H), ~x~mple 20 To a solution o:~ 10 g, of ethyl ~ ethoxyimino--(2-hydroxythia~;ol-4-yl)acetate in 30 m~,of e-thanol is added a solution of 11.47 g.of KOH in 5C) m~.of water at room temperature and the mixture is stirred for 25 minutes.
The reaction mixture is condensed under reduced pressure and is made acidic with 10 % aq, Hcæ. Ethyl acetate extract of the reaction mixture is extracted with 10 ~0 aq,NaHCOz. The aqueous layer is then made acidic with 10 %
aq.HC~ and extracted again with ethyl acetate. From the ethyl aceta-te extract, after being washed, dried and ~2~1L62E~
condensed is obtained a crysta]line substance. Recrystal-lization from benzene-ethanol gives a-ethoxyimino-(2-hydroxythiazol-4-yl)acetic acid. 7.5 g. Melting point:
1~1.5C (dec.)O
AnalysiS - Galcd. for C7H80~LN2S
C, ~8-88; Ht 3.72; N/ 12.95, Found: C, 38.65; H, 3 85;
N, lZ.06.
NMR(ppm! 100 MHz, d6-DMSO): 6.64(1H,s,5-H).
Example 21 To a mixture of 1 g,of a-ethoxyimino-(2-hydroxy-thiazol-4-yl)acetic acid, 10 mR,of 50 % aq. formic acid and 5 mR.of methanol is added gradually G.9 g~of zinc dust under ice-cooling. ~he mix-ture is stirred for 1 hour at this state and then for ~0 minutes at room temperature.
The re&ction mixture is filtered and the filtrate is passed through a column packed with ion-exchange resin (Amberlite IR-120(H)) to give purified 2-hydroxythiazol-4-ylglycine.
Analysis - Calcd; for C5H60~N2S:
N, 16.08, Foun~: N, 15.96 N`MR(ppm, 100 MHz, C~COOD): 5.56(1H,s, `CH~COOH)~ 6.91 (1~, s,~
~xample 2?
~ 'o a mixture of 40 mR~of C-HCR and 100 mR.of water is dissolved under ice--cooling 8.8 g~of ethyl a-oxyimino-(2-aminothiazol-4-yl)acetate. A solution of 2.8 gOof Na~02 in 20 mROof water is added dropwise to this solution in a period of 20 minutes. After being stirred for 2.5 hours under ice cooling the reaction mixture is ex-tracted with ~00 m~.of ethyl ace-tate. The ex-tract is washed wi-th water and dehydrated. The ethyl acetate is distilled off and the resultant oil is purified by silica gel chromato-graphy to give ethyl ~-oxyimino-(2-hydroxythiazol-4-yl)-acetate.
NMR(ppm, 100 MHz, CDC~3): loZ7(~H,t,CH2C ~ ), 4,36(2H,q, CH2CH3), 8.02(lH,s,5-H).
Example 23 To a solution of 1.3 g.of ethyl ~-oxyimino-(2-hydroxythiazol--4--yl)acetate in 5 m~.of e-thanol is added under ice-cooling Z0 m~Oof 50 /c aq. formic acid. Zinc dust (1.17 gO) is added gradually to this solution in a period of 5 minutes under stirring. The reaction mixture is stirred for 2 hours under ice-cooling and filtered.
The filtrate is condensed under reduced pressure and the residue is poured into 10 m~.of wa-ter. The wa-ter layer is neutralized with 10 % aq. NaHC03 and then extracted with ethyl acetate. The extrclct is washed wi-th water and dehydrated~ The ethyl aceta-te is distilled off and the resultant oil is purified by silica gel chromatography to g,ive ethyl 2-hydroxythiclzol-4-ylglycine.
NMR (ppm, 100 MHz, CDC~3): 1.22(ZH,t,-CH2CH3)1 4,27(2H,q, -CH2CHz), 4.65(lH,s, ,CH-COOC2H5), 7014(lH,s,5-H).
The ester is acylated with ~,,3,~-trichloro ethyl chloroformate in CH2C~2 in the presence of triethylamine to give ethyl ~ 3,13,~--trichloroethoxycarbonylamino)-(~-hydroxy-thiazol-4-yl)acetate.
3L2~ 84 Analysis - Calcd for CloHll05N2SC~3:
N, 7.~Ll; ~ound: N, 7.39 ~MR(ppm, lO0 MHz, CDC~3): 1.26(3H,t7-CH2CH ) 7 4.2?(2H,q, -CH2CH3), 4.70(2H,s,C~zCCH2), 5042(1H,d, `CH-COOC2H5), 7024(1H,s,5-H).
xample 24 To a solution of l.9Z g.of eth-yl ~ oxyimino-~-oxo-y--chlorobutyrate in lO m~Oof ethanol is added 1027 g.of ethylthionocarbamate and the mixture is heated for 2 hours under reflux. After cooling ethanol is evaporated then the remaining oily subs-tance is purified by means of silica gel chroma-tography to give ethyl a-oxyimino-(2-hydroxythiazol-4 yl)ace-tate. The ester is identical with the substance obtained in Example 22 in all respects.
xample 2~
To a solution of 2 65 g of ethyl a-acetamido-~-oxo-Y-bromobutyrate in lO m~.of ethcmol is added 1.09 g.
ot` methylthionocarbamate. The mixture is heated for 1.5 hours under reflux and concentrclted under reduced pressure.
The concentrate is dissolved in chloroform. The chloro-form layer is washed, driecl and concen-trated to give e-thyl ~-ace-tamic'o (2-hydroxythiazol-4-yl)ace-tate as oily material This ester (2.0 g ) is dissolved in lO m~.of methanol and to this is added a solution of 3.09 ~ of Ba(OH)2 8H20 in 50 m~.of water and the whole mix~ure is stirred at 70C
for 3 hours. After cooling, gaseous C02 is bubbled into the reaction mixture to cause precipitation of BaC03 BaC03 2~3~
thus precipitated is filtered off and the filtra-te is passed through a column packed wi-th ion-exchange resin ~Amberlite I~,-120(H)) to give purified 2-hydroxythiazol-4--ylglycine, This substance is identical wi-th the sample obtained in ~xample 21 in all respects.
xample 26 To a solution of 2,2 g.of ethyl a-methoxyimino-~-oxo-~-bromobutyrate in 40 mROof ethanol are aclded 1,~2 g.
of dimethylaniline and 2.? g.of N-(6,~,,B~trichloroethoxy-carbonyl)thiourea. The mixture is heated for 1.5 hours under reflux and concentrated under reduced pressure. The concentrate of the reaction mixture is recrystalliæed from ligroin to give ethyl a-methoxyimino-(2-(~9~9~-trichloro-ethoxycarbonylamino)thiazol-4-yl)acetate as crystals. 1.~4 g.
Melting point: 125-128Co Analysis - CalcdO for CllHl205N2SCR3 C, Z2.~5; Hl 209~; Ng 10~38. Found: C, 32.~1;
Hl 3.14; N, 10019.
~MR(ppm, 100 MEI~, CDC~3): 7.15(1H,s,5-H), ~xample 27 To a solution of 801 g.of e-thyl a-methoxyimino-(2-~ -trichloroethoxycarbonyl~lino)thiaæol-4-yl)acetate in 50 mR.of ethanol is added a solution of 1102 gOof KOH in a mixture of ~0 m~.of water and 150 m~Oof ethanol. The whole mixture is stirred at room temperature for 1 hour, and tL~en concentrated under reduced pressure, The residue is extracted with ethyl acetateO The water layer is made _ L~3 _ ~Zl~Z~4 acidic with 10 % aqO HC~ and the separated solid is collected, Recrys-tallization of -the solid from aq. me-thanol gives a-methoxyimino-~2~ trichloroethoxycarbonyl-amino)thiazol-4-yl)ace-tic acid, 4 .1 g, Melting pOiIlt:
162-153~C.
Analysis - Calcd. for C9H805N3SC~6:
C, 28.70; H, 2~14; N, 11.16. ~ound C, 28.64;
H, 2.11; N, 11,06 NM~ (ppm, 100 MHz~ CDC~3+d6-DMS0): 7,26(1H,s,5-H).
~xamE~e 23 Ethyl c~-methoxyimino--~2-(~ --trichloroetho~ycarbonyl-amino)thiazol-4-yl]acetate (2.02 g.) dissolved in 150 m~.of ethanol containing 10 /0 HC~ is hydrogenated in the presence of 2,0 g,of 5 /0 Pd/carbon. hfter 240 m~of hydrogen is absorbed, the reaction mixture is filtered and the filtra-te is condensed under reduced pressureO ~he residue is washed with ether and suspended in 70 m~.of ethyl acetate followed by the acldition of 20 m~,of 5 Y aq. NaHC03, The e-thyl ~cetate layer is separated, washed, dried and condensed -to give ~2-(~ 7~ trichloroethoxycarbonyl&mino)thiazol-4-yl]glycine ethyl ester. 1,22 g.
AnalysiS - Calcd, for CloH120L~N35C~3 C, 31.89; H, 3.21j N9 11016. ~ound: Cg 31,91;
H, 3.00; N, 10.63 NMR(ppm, 100 MHz, CF3C00D): 5.82(1H,s, `CH-C00C2H5), 7.74(1H,s,5-H), L~4 _ ~Z~6;~
Example 29 (1) A solution of 19.3 g,o~ e-thyl a-oxyimino~-oxo-~chlorobutyrate and 8.0 g.of thiourea in 200 m~Oof ethanol is heated for 2 hours under reflux. The mixture is condensed under reduced pressure and the residue is dissolved in 10 /c aqO HC~. The solution is washed twice wi-th ether -to remove unreac-ted butyrate and is adjusted to pH 7.0-705 with NaHC0z Chloroform extraction of the mix-ture gives ethyl a--oxy-imino-2-aminothiazol-4-ylacetate, ~1.4 g~ Meltin~ poin-t:
lZ7-138C (dec.), Analysis - Calcd, for C7H903N3S:
C, 39.06; H, 4,21; N~ 19,52, Found: C, 39,64;
~I, 4.09; N, 19,62, IR(Nujol, cm 1): 3430(C=NOH) 3 1710(ester) (2) Ethyl a-oxyimino-2-aminothiazol~4-yl-acetate (2.15 g,) obtained in the foregoing part is dissolved in a mixture of 20 m~Oof 50 /0 aq, formic acid and 10 m~.o~ methanol.
To -this is added 1.5 ~;Oof zinc dust ~md tne mixture is stirred for 3 houx~s under ice-cooling, The filtered Ieaction mi,Y-ture is condensed under reduced pressure and the concentrate is passed through a column packed wi-th ion-exchange resin (Amberlite IR-120(H))o The column is washed with water to remove formic acid and then is eluted with 10 % aq, ammonia to give 2-amino-thiazol-4 yl-glycine,
hydroxythiazol~ yl)ace-tic acid in 20 m~ of absolute ether is added 1.25 gOof phosphorus pen-tachloride and the mix-ture is stirred for 2 hours a-t room temperatureO ~he acid chloride solution is dropwise added to a suspension of 1.80 gOof 7--aminocephalosporanic acid in 50 m~Oof N,N-dimethylacet.~ide and -the mixture is stirred for ~ hours at room temperature. The mixture is e~trac-ted 3 times with each 120 m~Oof ethyl acetate and the combined eY~trac-ts are washed with water and dried over anhydrous ma~nesi~u~
sulfate. The solvent is removed and the residue is dissolved in 60 m~ of 90 /0 aq. formic acid~ To the acidic solution is added 4,~0 ~;.of zinc dust at 0C and -the mixture is s-tirred for 2 hours at this temperature.
Insoluble material is filtered off and the filtrate is concentrated under reduced pressure, To the residue is added 20 m~.of water and hydrogen sulfide gas is bubbled through the aqueous solution for 5 minutes, Insoluble material is filtered off and the fil-trate is a~ain concen-t-rclted. The residlle is dissolved i~ 5 /0 sodium hydro~en carbonate aq. solution and purified with a column packed with Amberlite XAD-2. The fractions obtained by the eluation with 5 /~ aqueous ethanol is lyophilized to afford sodium '7~-(2-hydroxythiazol-4--ylglycyl~lido)-cephalosporanate, Analysis - Calcd. for C15H15N~07S2Na H20 C, 3~.46; H, 3~66; N7 11.96. ~ound: C, 38035;
H~ 4,04j N, 12.2~o ~xample 15 A solution of 10.0 g,of N~ -trichloroe-thoxy-carbonyl)thiourea, 12.0 gOof 1,l ,3-tribromoacetone and 5,0 g, of dimethylaniline in lO0 m~.of e-thanol is heatecl under reflux for 2 hours, After cooling9 e-thanol is re~noved under reduced pressure, and the oily residue is dissolved in ethyl aceta-te. Ethyl acetate layer is washed with water and dried over MgSOL,, :E~thyl acetate is removed under reduced pressure and the oily residue is dissolved in small quantity of chloroform. ~rom the solution which is allowed to stand at room temperature is obtained 2-( trichloLoethoxycarbonyl)amirlo-4-îormylthiazole as a crystalline form, 5.0 g. Melting point: 188-190C.
Analysis - Calcd. for C7H503N~ C~3:
C, 27.69; H, 1.66; N9 9.23. ~ound. C, 27.87;
H, 1.69; N! 9.01.
NMR (ppm, lO0 MHz, Cl~C~7~,-d~, LMS0);
5.05(2H,s,C~3CCH2--), 8.05(1H,s,5-H), 9.80(1H,s,CH0) ~ o a mixture of l,0 g~ of 2-(~7~ trichloroe-thoxy-cn:rbony'l)arnirlo-4-formyl-thiazo:le, 0.~7 F~o OI KH2P0~ mk70 of water and 4 m~0 of dimethylformamide is added 0.33 g, of KCN at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of ethyl acetate ~;ives ~-hydroxy--[2~ 3-trichloroethoxycarbonyl)aminothiazol-4-yl )--acetonitrile 1,127 g, NMR (ppm, 100 MHz, CDC~73): 4,90(2H9s,C~73CCH2-), 5.70 (lH,s7--CHCN), 7.90(1H9s,5H)o ~6~84 Example 17 To a solution of 1.10 g of a-hydroxy--(2-(~
trichloroethoxycarbonyl)aminothiazol-4-yl)ace-tonitrile in 1 m~-of pyridine is added 2.5 m~ of acetic anhydride under ice-cooling and the mixture is stirred for 1 hour. ~o the mixture is added ether and water and the organic layer is washed with aq NaHC03 and further water in this order.
Evaporation of ether gives a-acetoxy-~2~ -trichloro-ethoxycarbonyl)aminothiazol-4-yl)acetonitrile. 1 ~ g.
~MR(ppm, 100 MHz, CDC~3): 2 20(3H,s,C0CH3), 5 00(2H,s, CRzCCH2-), 6 60(1H,s, `CEICN), 7.30(1H,s,5 H) Example _18 To a solution of 1.30 g of a-acetoxy-~2-(~
trichloroethoxycarbonyl)aminothiazol~4-yl)acetonitrile in 10 m~.of methanol is bubbled gaseous hydrochloric acid for 10 minutes under ice-cooling, and the mixture is kept standing at room temperature for 1 hour. After eva-poration of methanol is added 40 m~.of 50 % aq methanol to the residue and s-tirred for 1 hour To -this reaction mixture is added 1 0 g.of NaOH and s-tirrecl for 1 hourO Methanol is removed under reduced pressure and the residue is extracted with ethyl aceta-te af`-ter being made acidic wi-th N-HC~
Ethyl aceta-te layer is washed with water and dried. ~thyl aceta-te is removed under reduced pressure to obtain a-hydro-xy-(2~ -trichloroethoxycarbonyl)amino)-thiazol-4-yl acetic acid. 0 995 g. Melting point: 135-136C.
~nalysis - Calcd for C8H705N2SC~3:
C, 27 48; H 2.02; N, 8 01. Found: C, 27.72; H, 2.05;
N, 8 08.
~ 38 -L6~
NMR(ppm, 100 MHz, CDC~3): 4,90~2H,S,c~3ccH2~) t 5-~0(1II,s~
,CH -COOH), 7.10(lH,s~5-H).
~xample 19 To a solution of 21,43 gO of ethyl a-ethoxyimino~
oxo-~-bromobutyrate in ~30 m~Oof ethanol is added 8081 g of methyl-thionocarbamate and the mixture is heated under reflux for 1.5 hours, A-ter coolin~; ethanol is removed under reduced pressure and the oily residue is dissolved in chloroform. The chloroform solution is washed, dried, and condensed. The condensate is purified by silica gel chromatography to give 11.9 g, of ethyl c~-ethoxyimino-(2-hydroxythiazol--4-yl)aceta-te. Mel-tin~ point: 54-55C.
Analysis - Calcd. for CgH1204N2S:
C, 44.25; H, 4,95; ~ 7. ~ound: C, 44.54; H, 5004;
~ i, 11.5~.
NMR(ppm, 100 MHz, CDC~ 6.Z3(1H,s,5-H), ~x~mple 20 To a solution o:~ 10 g, of ethyl ~ ethoxyimino--(2-hydroxythia~;ol-4-yl)acetate in 30 m~,of e-thanol is added a solution of 11.47 g.of KOH in 5C) m~.of water at room temperature and the mixture is stirred for 25 minutes.
The reaction mixture is condensed under reduced pressure and is made acidic with 10 % aq, Hcæ. Ethyl acetate extract of the reaction mixture is extracted with 10 ~0 aq,NaHCOz. The aqueous layer is then made acidic with 10 %
aq.HC~ and extracted again with ethyl acetate. From the ethyl aceta-te extract, after being washed, dried and ~2~1L62E~
condensed is obtained a crysta]line substance. Recrystal-lization from benzene-ethanol gives a-ethoxyimino-(2-hydroxythiazol-4-yl)acetic acid. 7.5 g. Melting point:
1~1.5C (dec.)O
AnalysiS - Galcd. for C7H80~LN2S
C, ~8-88; Ht 3.72; N/ 12.95, Found: C, 38.65; H, 3 85;
N, lZ.06.
NMR(ppm! 100 MHz, d6-DMSO): 6.64(1H,s,5-H).
Example 21 To a mixture of 1 g,of a-ethoxyimino-(2-hydroxy-thiazol-4-yl)acetic acid, 10 mR,of 50 % aq. formic acid and 5 mR.of methanol is added gradually G.9 g~of zinc dust under ice-cooling. ~he mix-ture is stirred for 1 hour at this state and then for ~0 minutes at room temperature.
The re&ction mixture is filtered and the filtrate is passed through a column packed with ion-exchange resin (Amberlite IR-120(H)) to give purified 2-hydroxythiazol-4-ylglycine.
Analysis - Calcd; for C5H60~N2S:
N, 16.08, Foun~: N, 15.96 N`MR(ppm, 100 MHz, C~COOD): 5.56(1H,s, `CH~COOH)~ 6.91 (1~, s,~
~xample 2?
~ 'o a mixture of 40 mR~of C-HCR and 100 mR.of water is dissolved under ice--cooling 8.8 g~of ethyl a-oxyimino-(2-aminothiazol-4-yl)acetate. A solution of 2.8 gOof Na~02 in 20 mROof water is added dropwise to this solution in a period of 20 minutes. After being stirred for 2.5 hours under ice cooling the reaction mixture is ex-tracted with ~00 m~.of ethyl ace-tate. The ex-tract is washed wi-th water and dehydrated. The ethyl acetate is distilled off and the resultant oil is purified by silica gel chromato-graphy to give ethyl ~-oxyimino-(2-hydroxythiazol-4-yl)-acetate.
NMR(ppm, 100 MHz, CDC~3): loZ7(~H,t,CH2C ~ ), 4,36(2H,q, CH2CH3), 8.02(lH,s,5-H).
Example 23 To a solution of 1.3 g.of ethyl ~-oxyimino-(2-hydroxythiazol--4--yl)acetate in 5 m~.of e-thanol is added under ice-cooling Z0 m~Oof 50 /c aq. formic acid. Zinc dust (1.17 gO) is added gradually to this solution in a period of 5 minutes under stirring. The reaction mixture is stirred for 2 hours under ice-cooling and filtered.
The filtrate is condensed under reduced pressure and the residue is poured into 10 m~.of wa-ter. The wa-ter layer is neutralized with 10 % aq. NaHC03 and then extracted with ethyl acetate. The extrclct is washed wi-th water and dehydrated~ The ethyl aceta-te is distilled off and the resultant oil is purified by silica gel chromatography to g,ive ethyl 2-hydroxythiclzol-4-ylglycine.
NMR (ppm, 100 MHz, CDC~3): 1.22(ZH,t,-CH2CH3)1 4,27(2H,q, -CH2CHz), 4.65(lH,s, ,CH-COOC2H5), 7014(lH,s,5-H).
The ester is acylated with ~,,3,~-trichloro ethyl chloroformate in CH2C~2 in the presence of triethylamine to give ethyl ~ 3,13,~--trichloroethoxycarbonylamino)-(~-hydroxy-thiazol-4-yl)acetate.
3L2~ 84 Analysis - Calcd for CloHll05N2SC~3:
N, 7.~Ll; ~ound: N, 7.39 ~MR(ppm, lO0 MHz, CDC~3): 1.26(3H,t7-CH2CH ) 7 4.2?(2H,q, -CH2CH3), 4.70(2H,s,C~zCCH2), 5042(1H,d, `CH-COOC2H5), 7024(1H,s,5-H).
xample 24 To a solution of l.9Z g.of eth-yl ~ oxyimino-~-oxo-y--chlorobutyrate in lO m~Oof ethanol is added 1027 g.of ethylthionocarbamate and the mixture is heated for 2 hours under reflux. After cooling ethanol is evaporated then the remaining oily subs-tance is purified by means of silica gel chroma-tography to give ethyl a-oxyimino-(2-hydroxythiazol-4 yl)ace-tate. The ester is identical with the substance obtained in Example 22 in all respects.
xample 2~
To a solution of 2 65 g of ethyl a-acetamido-~-oxo-Y-bromobutyrate in lO m~.of ethcmol is added 1.09 g.
ot` methylthionocarbamate. The mixture is heated for 1.5 hours under reflux and concentrclted under reduced pressure.
The concentrate is dissolved in chloroform. The chloro-form layer is washed, driecl and concen-trated to give e-thyl ~-ace-tamic'o (2-hydroxythiazol-4-yl)ace-tate as oily material This ester (2.0 g ) is dissolved in lO m~.of methanol and to this is added a solution of 3.09 ~ of Ba(OH)2 8H20 in 50 m~.of water and the whole mix~ure is stirred at 70C
for 3 hours. After cooling, gaseous C02 is bubbled into the reaction mixture to cause precipitation of BaC03 BaC03 2~3~
thus precipitated is filtered off and the filtra-te is passed through a column packed wi-th ion-exchange resin ~Amberlite I~,-120(H)) to give purified 2-hydroxythiazol-4--ylglycine, This substance is identical wi-th the sample obtained in ~xample 21 in all respects.
xample 26 To a solution of 2,2 g.of ethyl a-methoxyimino-~-oxo-~-bromobutyrate in 40 mROof ethanol are aclded 1,~2 g.
of dimethylaniline and 2.? g.of N-(6,~,,B~trichloroethoxy-carbonyl)thiourea. The mixture is heated for 1.5 hours under reflux and concentrated under reduced pressure. The concentrate of the reaction mixture is recrystalliæed from ligroin to give ethyl a-methoxyimino-(2-(~9~9~-trichloro-ethoxycarbonylamino)thiazol-4-yl)acetate as crystals. 1.~4 g.
Melting point: 125-128Co Analysis - CalcdO for CllHl205N2SCR3 C, Z2.~5; Hl 209~; Ng 10~38. Found: C, 32.~1;
Hl 3.14; N, 10019.
~MR(ppm, 100 MEI~, CDC~3): 7.15(1H,s,5-H), ~xample 27 To a solution of 801 g.of e-thyl a-methoxyimino-(2-~ -trichloroethoxycarbonyl~lino)thiaæol-4-yl)acetate in 50 mR.of ethanol is added a solution of 1102 gOof KOH in a mixture of ~0 m~.of water and 150 m~Oof ethanol. The whole mixture is stirred at room temperature for 1 hour, and tL~en concentrated under reduced pressure, The residue is extracted with ethyl acetateO The water layer is made _ L~3 _ ~Zl~Z~4 acidic with 10 % aqO HC~ and the separated solid is collected, Recrys-tallization of -the solid from aq. me-thanol gives a-methoxyimino-~2~ trichloroethoxycarbonyl-amino)thiazol-4-yl)ace-tic acid, 4 .1 g, Melting pOiIlt:
162-153~C.
Analysis - Calcd. for C9H805N3SC~6:
C, 28.70; H, 2~14; N, 11.16. ~ound C, 28.64;
H, 2.11; N, 11,06 NM~ (ppm, 100 MHz~ CDC~3+d6-DMS0): 7,26(1H,s,5-H).
~xamE~e 23 Ethyl c~-methoxyimino--~2-(~ --trichloroetho~ycarbonyl-amino)thiazol-4-yl]acetate (2.02 g.) dissolved in 150 m~.of ethanol containing 10 /0 HC~ is hydrogenated in the presence of 2,0 g,of 5 /0 Pd/carbon. hfter 240 m~of hydrogen is absorbed, the reaction mixture is filtered and the filtra-te is condensed under reduced pressureO ~he residue is washed with ether and suspended in 70 m~.of ethyl acetate followed by the acldition of 20 m~,of 5 Y aq. NaHC03, The e-thyl ~cetate layer is separated, washed, dried and condensed -to give ~2-(~ 7~ trichloroethoxycarbonyl&mino)thiazol-4-yl]glycine ethyl ester. 1,22 g.
AnalysiS - Calcd, for CloH120L~N35C~3 C, 31.89; H, 3.21j N9 11016. ~ound: Cg 31,91;
H, 3.00; N, 10.63 NMR(ppm, 100 MHz, CF3C00D): 5.82(1H,s, `CH-C00C2H5), 7.74(1H,s,5-H), L~4 _ ~Z~6;~
Example 29 (1) A solution of 19.3 g,o~ e-thyl a-oxyimino~-oxo-~chlorobutyrate and 8.0 g.of thiourea in 200 m~Oof ethanol is heated for 2 hours under reflux. The mixture is condensed under reduced pressure and the residue is dissolved in 10 /c aqO HC~. The solution is washed twice wi-th ether -to remove unreac-ted butyrate and is adjusted to pH 7.0-705 with NaHC0z Chloroform extraction of the mix-ture gives ethyl a--oxy-imino-2-aminothiazol-4-ylacetate, ~1.4 g~ Meltin~ poin-t:
lZ7-138C (dec.), Analysis - Calcd, for C7H903N3S:
C, 39.06; H, 4,21; N~ 19,52, Found: C, 39,64;
~I, 4.09; N, 19,62, IR(Nujol, cm 1): 3430(C=NOH) 3 1710(ester) (2) Ethyl a-oxyimino-2-aminothiazol~4-yl-acetate (2.15 g,) obtained in the foregoing part is dissolved in a mixture of 20 m~Oof 50 /0 aq, formic acid and 10 m~.o~ methanol.
To -this is added 1.5 ~;Oof zinc dust ~md tne mixture is stirred for 3 houx~s under ice-cooling, The filtered Ieaction mi,Y-ture is condensed under reduced pressure and the concentrate is passed through a column packed wi-th ion-exchange resin (Amberlite IR-120(H))o The column is washed with water to remove formic acid and then is eluted with 10 % aq, ammonia to give 2-amino-thiazol-4 yl-glycine,
9 g, ~ecrystallization from aq. ethanol gives pure sample; Melting point: 186 190C(dec,), Analysis - Calcd. for C5H702N3S 1~2H20:
C, 32.96; H, 4O~3; ~ 23,06, Found: C~ Z2,94; H, 4,61;
N, 22.22 ~Z~I 34 NM~(ppm, 100 ~-Iz, CF3COOD): 5.25 (lH,s, ,CII-COOH), 6.75 (lH,s,5-H), Violet color with Ninhydrin rea~entO
Example ,~0 __ A solution of 19,3 g,of thiourea an~ 5Zo5 g~of e-thyl ~-oxyimino-~ oxo-y-chlorobu-tyrate in 300 m~Oof ethc~lol is stirred for 3 hours at room temperature, and condensed under reduced pressure. Water ~200 m~.) is added to the residue and the ob~ained aqueous solution is washed twice with ether. To this are added 130 m~of 85 /c aq. formic acid and 150 mR.of ethanol. Under ice-cooling ~7 g.of zinc dust is aclded gradually to this mix-ture and stirred for 3 hours at room temperature.
The filtered reaction mixture is passed through a column packed wi-th ion-exchange resin (Amberlite 1~-120(H)).
The column is washed wi-th water and eluted with 10 Y aq.
ammonia to give purified 2-amino-thia~ol-4-ylglycine (27.5 g.) which is iden-tical with the sc-~ple obtained in hxc~mple ~9 in all respects.
Exc~mple_ 31 Ethyl ~-oxyimino-2-aminothia~;ol-4-ylacetate hydro--chloride (503 mg~ is dissolved in 10 m~Oof 50 O/G aq.formic acid and 5 m~.of ethanol. Zinc dust (300 mg.) is added to -this solution under ice-cooling and stirred for 3 hours.
The reaction mix-ture is condensed under reduced pressure below 30C, and the residue is made pH 7,5 by adding lN-NaOH. Ethyl acetate extraction gives 2-aminothiazol-4-~2~6;~
ylgl-gcine ethyl ester. 130 mg, N~R(ppm, 60 ~iHz, C~zCOOD): 1,0'~3H,-t,-CH2C ~ )~ 4o18( 2H,q~
-CH~CH3), 50Z5(lH 7 S, , CH-C0~2Hr,)~ 6090(lH,s,5-H).
Mass: m/e 201,0549(theoretical: 201,0571) Example ~2 To a solutisn of 26.6 g.of ethyl a-acetamido--,B-oxo-y-bromobutyrate in a mixture of 50 m~Oof ethanol and 20 m~.
of ether are added 9 o 14 g.of thiourea and 15 m~Oof pyridine.
The mixture is stirred for 1 hour at room temperature and then 4 hours under reflux. The reaction mixture is condensed under reduced pressure and 5~ m~.of ethyl aGetate is added to the residue. The mixture is extrac-ted with 3N-HC~, The water layer thus separated is made pH 10 by adding lN-NaOH and extracted with ethyl acetateO
The ethyl aceta-te extract is washed9 driecl and con-densedO To this concentrate is added small ~uantity of chloroform to cause crystallization of ethyl ~-acetamido-2-amino-thiazol-4-ylacetateO 7.0 g. Melting point: 161,1C.
Analysi~ - Calcd. f'or C9H1303N;~S:
C, 44.43; H, 5.39; N, 17.27. Found: C, 44046; H, 5.24;
N, 16.99 xample 33 To a solution of ~406 gOof ethyl ~-acetamido-~-oxo-r-promobutyrate in a mixture of 50 m~Oof ethanol and 20 m~.of ether are added 1809 gOof N-acetylthiourea and 15 m~Oof pyridine. The mixture is heated under reflux for 4 hours, and condensed under reduced pressure, The condensate is extracted with ethyl ace-tate and the extrac-t ~6~8~
is washed with 5 % aq NaHCO~, then with water, and driedO
The oily substance which is ob-tained from the extract by removal of the solven-t is purified by silica gel chromato-~;raphy to giVQ e-thyl a-acetamido-2- acetamidothiazol-L~-ylacetate. 4 46 gO Melting point: 14809-150C.
Analysis - CalcdO for CllH15C4 3 2 C, 45 59j H, 5 39; N, 14.500 Found: C, 45 73;
H, 5.40; N, 14021 _a ple 34 To a solution of 2 51 goO:E N-(~ -trichloroethoxy-caroonyl)thiourea c~nd 2 66 g of e-thyl a--acetamido-~-oxo-~-bromobutyra-te in 50 m~Oof ethanol is added 108 gOof N,N-dimethylaniline. The mixture is stirred for 24 hours a-t room tempera-ture, and condensed under reduced pressureO
The residue is dissolved in 30 m~.chloroform and the solu-tion is washed with 3N-HCR, water, and driedO ~he solid matter which is obtained by removal of chlo:rof`o:Lm is purified by sil:ica gel c~hroma-tography to give e-thyl a-acetamido-2-(~113,~-trichloroethoxycarbonylamino)thiazol-4-ylacetate 1 43 g Melting point: 161 9C
Analysis -- Calcd. for C12H14G5 3 3 2 C, 33.'70; H, 3.54; N, 9 82. Found: C, 33.69;
H, 3.64; N, 10.()6 ~M:~(ppm, 100 MXz, d6-DMSO): 1 15(3H,t,-CH2C~)~ 4.09(2H,g, -CH2CH3), 1.88(3H,s9COCH3), 4 96(2H,s,C~3CCH2), 5042(1H,d, ,CHCOCC2~5), 7.1~(1H,s,5-H) ~2~84 Example _~5 To a suspension of 100 mg of ethyl ~-acetamido-2-(~, ~ trichloroethoxycarbonylamino)thiazol-4 ylacetate in 5 m~ of water is added 2 m~.of lN-NaOH and -the mixture is stirred for 2 hours at room temperature. ~he reaction mixture is washed with ethyl acetate and -the water layer is made pH ~.0 with lN-HC~, and then extracted with ethyl acetate The extract is washed, dried 3 and condensed to give l~-acetyl-2~ trichloroethoxycarbonylamino~-thiazol-~-ylglycine. 65 mg. Melting poiNt: 158 ~C.
Analysis - Calcd. for CloHloO5N3 3 2 C, 30.05; H, 2.77; N, 10.51. ~ound: C9 30 15;
H, 2.52; N, 10.23~
NMR(ppm, 100 MHz, d6-D~I~0): 1.89(3H,s,COCH2), 4o97(2H,s, CRzCCH2), 5.40(1H,d, _CHCOOH), 7.10~1H,s,5-E~).
Example 36 To a solution of 238 mg.of e-thyl a-oximino-~-oxo-~-bromobutyrate in 10 me.of ethanol is ~dded 251 mg.of N-(,~,'3,~3-trichloroetho~ycclrbonyl)thiourea and the mixture is heated under reflux for 6 hours After cooling 3 50 m~Oof chloroform is added and the organic solu-tion is washed with water and dried over anhydrous magnesium sulfateO Evapora-tion of the solvent followed by chromatographic purification on silica gel affords 164 mg of ethyl ~-oximino-~-~2-(~
~--trichloroethox~calbonylamino)thiazol-4-yl)acetate.
Analysis - Calcd for CloHloN305$CR3 C, 30 74; H, 2058; N, 10 75; C~, 27~23 ~ound:
C, 30.95; H, 2.51; N, 10075; C~, 270020 ;Z8~
NM~(ppm, 100 MHz, CDCR3): 1035(ZH,t,C ~ CH2), 40Z6(2H,q, CH3CH2), 4 87(2H7s,C~3CCH2), 7O9LL(lH,s1-thiaæole ring proton).
~ xample 37 A solution of 2.0 gcof ethyl a-oximino-a-(2-(~-3~,C3-trichloroethoxycarbonylamino)thiaæol-4-yl)aceta-te in 50 m~.
of 10 % HC~-e-thanol is hydrogenated o~er 005 g.of 5 y palladium-on charco~l un~er shakingO The reaction stops when 90 m~Oof hydrogen is absorbed Additional 1.5 g of the catalyst is added and 170 m~Oof hydrogen is absorbed.
Insoluble material is filtered off and the filtrate is concentratecl under reduced pressure '~he residue is washed with e-ther, and separated q'he separated solid is dissolved in 5 m~.of water and neutralized with 10 % sodium hydrogen carbonate aq. solution, and then extracted with chloroformO
The extract is w~shed with water, drying over ~nhydrous magnesium sulfate and subjected to the evaporation of the sol~ent. '~he resultant residue is followed by chromato-graphic purifica-tion on silica gel column -to afford 560 mg.
of 2-(~,~3,~3-trichloroethoxycarborlylamino)thiazol-4-ylglycine ethyl ester.
Analysis - Calcd, for CloH12N30L~SC~3 C, 31.89; H, 3.21; N, 11.16 Found: C, 31.91 H, 3.0G; N, 10O63.
~IR(ppm, 100 MHæ, CF3C02D): 1.37(3H,t,CHzCH2), 4 47(2H,q, CH2CH~), 4.98(2H,s,C~3CCH2), 5 82(1H,s,CH), 7 0 74 (lH,s,thiazole ring proton).
- 5 ~
628a~
:Example ~8 ~ o a solution of 3 4U g.of 2~ trichlc>roethoxy-carbonylamino)thiazol-4-ylglycine ethyl es-ter in 50 m~ of chloroform are added gradually 1.2 gOof triethylamine and 2 50 g.of ~,13,~-trichloroethoxycarbonyl chloride under stirring at room temperature. After 30 minutes stirring, 100 m~O of chloroform is added to the mixture and the obtained organic solution is washed with saturatecl NaC~ aq.
solution, lN~hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate. Af-ter the evapo-ration of the solven-t n--he} ane is added to the residue to afford crude product. The crude product is recrystallized from a mixture of li~sroin and n--hexane to give ~ 11 g~ of 2- (,B,~ trichloroethoxycarbonylamino)thiazol-4-yl-N-(B, ~,13-trichloroethoxycarbonyl)glycine ethyl es-ter Yield 82 ~.
Analysis - Calcd. for C13H13N~065 6 C1 28.28; H, 2037; N ~ 7061. Found: C~ 28 39;
H, 2.~8; N, 7.71 N~ (ppm, 100 MHz, CDC~3): 1 21(3H,t,CH~;CH2), 4060~2H,q, CH3CH2), ~ 83 and ~86(~H~two s, C~3CCH2), 5.60~1H,d, CH), 6 98(1H,s,thiazole ring proton)~ 7u38(1H,d,a-NH).
Example 39 ~ o a solution of 3~82 gO of 2-(~ trichloroethoxy-carbonylamino)thiazol-4-yl-N~ -trichloroethoxycarbonyl)-glycine ethyl ester in 150 m~ of ethanol is added a solu-tion of 1.94 gO of potassium hydroxide in 10 m~O of water while stirring at room temperature. After 30 minutes stirring, the solution is concentrated under reduced pressure ~6Z8~
and 50 m~.of water is added to the residueO The aqueous solution is washed with ethyl aceta-te, adjusted to pH 2.0 with l~-hydrochloric acid and extracted twice each with 70 m~.of ethyl acetate. The combined extrac-ts are washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressureO n--Hexane is added to the residue to separate crude materialO The crude material is recrystallized from a mixture of ethyl acetate and ligroin to afford 1.83 g.of 2~ trichloroethoxy-carbonylamino)thiazol-4-yl-N~ -trichloroethoxycarbonyl)-glycine Yield 50 h NMR(ppm, 100 MH~, CDC~3): 40~0(4H,s,C~3CCH2~ 4065(1H,s, 2 NH), 5 4~(1H,broad d, C~), 6 14(1H broad d,a-N~I), 6 95(1H,s thiazole ring proton).
Example 40 To a suspension of Xo46 g.of 2-aminothiazol ~--yl-glycine in 100 m~Oof N,N-dimethylacetamide is added dropwise 12 6~ gOof ~,B,~--trichloroethoxycarbonyl chloride while stirring for 30 minutes at room temperatureO After further 30 minutes stirring, 250 m~Oof ethyl acetate is added to the reaction mixture and -the resulting solution is washed with 70 m~.o~ lN-hydrochloric acid ~he ethyl acetate is separated and extracted 3 times with 50 m~of 3 ~0 ag.
potassium hydroxide solution. The combined aqueous extracts are washed with ethyl acetate, adjusted to pH 200 with 1~-hydrochloric acid and extracted 3 times each with 100 m~ of ~L6~8~
ethyl acetate. The combined extracts are washed wi-th wa-ter, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, n-Hexane is added -to the oily residue to precipita-te c~ude material. Crude material is separated and recrystallized from a mixtllre of ethyl acetate and ligroin to afford 510 mg.of 2-(~9~,3-trichloroethoxy-carbonylamino)thiazol--4-yl N~ -trichloroethoxycarbonyl)-glycine. This product is identical with the compound obtained in Example 39 in all respects.
Example 41 To a suspension of 2.4 g.of 7--~mino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3--cephem-4-carboxylic acid in 20 mR.of dimethylacetamide is added 2,4 g.of ~-hydroxy-2-~ ,,B-trichloroethoxycarbonylamino)thiazol--4-ylacetic acid cyclic carboxy anhydride (obtained by the procedure described in ~xample L~) and the mixture is stirred for 15 houxs at room -temperature, Ethyl acetate (100 mR.) is added to -the reaction mixture and filtered, The filtrate is ex-tracted several times with 5 % aq. NaHC03, The combined extract is adjusted to pH 3.0 with 10 % aq. HC~ and extracted with ethyl ace-tate, The ethyl acetate layer is washed with saturated aq, NaCR and dried, Evaporation of the solvent gives 7~- {~-hydroxy-(2-(~9~ trichloroethoxycarbonyl-amino)thiazol-4-yl)acetamidoJ -3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4 carboxylic acid (1.8 g.) as a jelly which is then dissolved in 100 mR. of 90 /c aqc formic acid under ice cooling. To this solution is added 1,8 gO
of zinc dust and stirred for 1 hour under ice-cooling.
~Z1~2B~
The reaction mixture is filtered and condensed under reduced pressure. Water (100 m~ is added to the condensate and H2S gas is bubbled into the aqueous solution to precipitate zinc sulfide. Zinc sulfide is filtered off and the fil-trate is condensed under reduced pressure and the concentrate is dissolved in 5 % aq. NaHC03 solution and the solution is passed through a column packed ~ith polystyrene resin (Amberlite ~AD-2) to give purified 7B~(a-hydroxy-a-(2--aminothiazol '~-yl)acetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt.
Analysis - CalcdO for C15H1505NgS3 3 2 C, Z2.14; H, 3 78; N, 19.99. Found: C, 32.53;
H, 3.77; N, 19.50.
NMR(ppm, 100 M~lz, D20): 3.71(2H,q,2-CH2), 4.14(3H,s~N-CH~), 5.28(1H,s,~ CH-CO~H)~ 5.22(1H,d,6~H) 7 5 75(1H,d,7-H), 6 84(1H,s,5-H).
xample 42 To a solution of 100 8 mg~of NaHC03 ~nd 127 ~ mg.of 5-mercapto-l~methyl--lH-tetraæole in 10 m~.of water is added 486 mg.of sodium 7~ hydroxy-(2-aminothiazol-4-yl)acet-amido)cephalosporana-te. The mixture is stirred at 55C for 20 hours. After cooling the mixture is passed through a column packed with polystyrene resin (Amberlite XAD-2) to give purified sodium 7~-~a-hydroxy--(2-aminothiazol-4-yl)-acetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate, which is identical with the sample obtained in ~xample 41 in all respects _ 5~ _ ~2:1iZ8~
Example 43 To a suspension of 781 mg~of a~ethoxyimino-(2-( trichloroethoxycarbonylamino)thiazol 4-yl)acetic acid in 15 m~Oof CH2C~2 is added 625 mgOof phosphorus pen-tachlo-ride. ~he mixture is homogenized by stirrin~ for 10 seconds. After stirring at room -temperature for 1 hour, the solvent is removed under reduced pressure and the residue is dissolved in 10 m~.of acetone, On the other hand 7-amino-3-(1-methyl-lH-tetrazol--5-ylthiomethyl)-3-cephem-4-carboxylic acid (657 mg.~ and ~aHC03 (1.68 ~) are dissolved in a mixture of 20 m~.of water and 10 mæ~of acetone. To this solution while ice-cooling, the foregoing acetone solution is added dropwise in a period of 3Q millutes.
After the dropping, the mixture is stirred at room tempera-ture for 2 hours, and condensed under reduced pressure to remove acetone. The concentrate is washed with ethyl acetate, adjusted to pH 2.0 with lN-HC~ and extracted with ethylacetate, The ethyl acetate e~tract is washed with water, clried over anhydrous magnesium sul~ate and condensed to give 7~ -etho~yimino (2-(~ trichloroethoxycarbonyl-~ino)thiazol-4-yl~acetc~idoJ ~ l-methyl-lH-tetrazQl-5-ylthiomethyl)-3-cephem-4-carboxylic acid. 925 mg. Yield 66,0 %.
NMR(ppm, 100 MHz CF3COOD): 1 50~3H,t,CH~CHz), 4.60(2H,q, -CH2CH3), 3.85(2H~q,2-CH2), 4.12(3H s,~-CH3), 4.98 (2H,s,C~CCH2-), 5 38(1H d,6-H), 6002(1H,q,7-H), 7.91(1H,s,5-H)~
` 1~162~4 Example 44 Sodium 7,B- ~ a-ethoxyimino-(2-(,B,~,~-trichloroethoxy-carbonylamino)-thiazol--4-yl)acetamido~ cephalosporanate (667 mg,) NaHC03 (90 mg.)and 5-mercapto-1-methyl-lH-tetra-zole (120 mg.)are dissolved to 20 m~Oof water, The mix-ture is stirred at 60C for 8 hours and filtered, ~he filtrate is adausted to pH 2,0 with lN-HC~ and the solid is separated.
The separated solid is filtered, washed with water and dried over phosphorus pentachloride under reduced pressure to give 7~ a-ethoxyimino-(2-(,B~,B,,B-trichloroethoxycarbonyl-amino)thiazol-4-yl)acetamidoJ -3-(1-methyl-lH-tetrazol-5--ylthiomethyl)-~-cephem--4-carboxylic acid~ (238 mg.)which is iden-tical with the sample obtained in ~xample 43 in all respects.
-- 5~ -~ ~6Z~34 To a suspension of 2 92 ~ of ~-ethoxyimino-(2-(chloroace-tamido)thiazol-4-yl)acetic acid in 50 m~ of methylene chloride is added 2 Q8 g of phosphorus penta-chloride. ~he mixture is stirred for 2 hours at room temperature, after which time methylene chloride is distilled off and the redisue is dissolved in 30 m~ of acetone The acetone solution is added dropwise under ice-cooling in a period of 15 minutes, to the solution of 3.29 g of 7-amino-3-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-lic acid and 804 g of sodium bicarbonate dissolved in a mixture of lO0 m~ of water and 50 m~ of acetone Af-ter the addition has been completed, the obtained solution is stirred at room temperature ~or 2 hours and concentrated under reduced pressure to remove aceto~eO ~he concentrate is washed with ethyl acetate and adjusted -to pH 2.0 with 3N
hydrochloric acid under ice-cooling, followed by ex-tracting with ethyl acetate ~he ethyl acetate layer is washed with water and dried o~er anhydrous magnesium sulfate, followed by distillatlon of the solverlt to give 3 80 g of 7~
ethoxyimino-l2-(chloroacetamidG~thiazol-'~-yl)acetamidoJ -3-(l-methyl-lH-te-trazol-5-ylthiomethyl)-3-cephem '~-carboxylic acid. Yield 63 1 %
NMR(ppm, 60 MHz, d6-DMS0~: 1034~3H,-t,CH~CH2-), 3 56(2H, broad S,2-CH2), 3.~5(3E,S,N-CH3), 4 05~ 50(4H,m, CH3CH2- and 3-CH2), 4.24i2H,S,C~CH2C0), 5~04ilH,d, 6-H), 5.70(1H,d,7-H), 7 82(]H,S, thiazole ring pro-ton).
IR(KBr,cm 1): 1760(~-lactamj, 1035~=N-0-C)o - ~7 -6~8 Example ~L6 To a solution of 3 90 g of sodium 7~ a-ethoxyimino-~2-(chloroacetamido)thiazol-4-yl)acetamido J -3-(1-rnethyl-lH-tetrazol-5-ylthiomethyl)-~-cephem-4-carboxylate in 50 m~
of water is added 1.52 g of thiourea. The mixture is stirred at room temperature for 3 hours and adjusted to pH 2 0 with lN hydrochloric acid. The resulting precipitates are filtered,washed with water and dried to obtain 2.L~0 g of 7~ -ethoxyimino-(2-aminothiazol-4-yl)acetamido1-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Yield 7~.1 ,~.
NMR(ppm, 60MHz,d~-DMS0): 1.26~H,t,GH3CH2~ .84~3H,~, ~ -CH3), ~.90-4 40~H,m,CH~CH2- and 3-CH2), 5.02(1H, d,~-H), 5.70(1H,d,7-H), 7.94~1H,S,thiazole ring proton).
I~(KBr,cm ~ ?70 ~-lactam), 1030(=N-0-C) ~xam~le 47 2.0 g of 7~ -ethoxyimino-~2-aminothiazol ~-yl)-acetamidol-~-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-cclrbo~lic acid is dissolved in 50 m~ o~ 90 ~
f`olmic acid. To the solution is added 2048 g of zinc dust under stirring and cooling at the temperature of -10C, and the mixture is further stirred for 15 minutes. Af-ter the reaction has been completed, the insoluble materials are filtered off. Into the f`iltrate is poured ether to precipitate white solid, which is centrifugally separated and washed three times with ether and dried ~yield; 1o66 g)O
This whi-te solid is dissolved in aq. solution of sodium bicarbonate. The solution is subjected to the purification L6~84 using a column of Amberlite XAD-2 and the fractions eluted with water are lyophilized to obtain sodium 7~-((2-c~mino-thiazol-4-yl)glycylamido)-3-~1-me-thyl-lH-tetrazol-5-yl-thio-methyl)-3-cephem-4-carbox~late.
NMR(ppm, lOOMHz,D20): 3.~4(3H,~,~-CH3), 6.74(1H,S,thiazole ring proton).
IX~Br,cm 1): 1760(~-lactam).
UV(~20, nm): 260(cephem) Example 48 (1) ~o a suspension of 6.25 g of phosphorus pentachloride in '~5 mR of anhydrous methylene chloride coolecl at -10C, is added 20 mR of anhydrous methylene chloride solution containing 2.4 g of pyridine and the mixed solution is stirred for 30 minutes ~o the solution is dropwise added a solution of 9.3 g of 7~-~2-thienylacetamido)-3-~1-methyl-lH-tetrazol-5-ylthiomèthyl)-3-cephem-4-carboxylic acid benz-hydryl ester in 30 mR of anhydrous methylene chloride during 30 minutes under stirring and keeping a-t -2C~ 10C. lhe mixture is further stirred for 2 hours at the sc~ne tempera-ture and then eooled to -30C - -20C, followed by adding dropwise 56 m~ of methanol. ~hus obtained solution is stirred for 30 minutes, keeping the temperature of the solution between -5C and 5C, and 60 mR of water is added dropwise thereto, followed by further stirring for 30 minutes Methylene chloride layer is washed with saturated aq. NaCR solution and concentrated. To the concentrate is added a mixture of water and ethyl acetate under stirring to give 4.746 g of 7-amino-3-~1-methyl-lH-tetrazol-5-ylthio-~ 59 -~LZ~6~8~
methyl)-3-cephem-4-car~oxylic acid benzhydryl ester as a crystal Yield 64.0 /, ~2) To a suspension of 2.05 g of ~-ethoxyimino-~-(2-( chloroacetamido)thiazol-4-yllacetic acid in 50 m~ of methylene chloride is added 1.50 g of phosphorus penta-chloride under cooling. ~he mixture is s-tirred for 2 hours at room temperature and subjected to the distillation of methylene chloride. ~he residue is dissolved in 20 m~
of tetrahydrofuran The tetrahydrofuran solution is dropwise added while stirring to a solution of 2,92 g of 7-amino-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carbo~ylic acid benzhydryl ester dissolved in 50 m~ of absolute methylene chloride, followed by the addition of 2,87 g of pyridine uncler ice-cooling. After the addition has been comple-ted and -the temperature of the reaction solution becomes the same as -the room temperature~ the solution is stirred for 2 hours and then concentrated, The residue is dissolved in a mixture of 100 m~e of e-thyl acetate and a little amount of tetrahydrofuran, ~hus ob-tained solution i5 washed with dilute hydrochloric acid, sodium bicarbonate aq. solution and water in this order, dried over anhydrous magnesi~ sulfate and conceIltrated. The concentrate is puri~ied by means of a column of silica gel, ~he fractions eluted with the mixture of ethyl ace-tate and chloroform (1:1) are concentrated to obtaiIl 2.36 g of 7~ -ethoxy-imino-~2-(chloroacetamido)thiazol-4-yl)acetamido,, -3-~1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid benzhydryl ester. Yield 50 /c.
~ÇiZ8~
NMR~ppm, 60MHz, CDC~ lU34(3H,t,CHj5CH2-), 3 68(2H,broad S,~-CH2), ;~.8o(~H~s~N-cH3), 4.26(2H~SsC~CH~C0), 5.04~1H,d,6-H), 5 92(1H,q,7-H), 6.94~1H,S,-CHPh2), 7.20-7.60(10H,m,Ph2), 7.90(1H,S,-thiazole ring prc-ton), 8.45(1H,d,7-~H).
xample 49 r~O a solution of 2.2 g of 7~- a-etho~yimino-~2-(chloroacetamido)thiazol-4-yl )acetamido -3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benz-hydryl ester in 20 m~ of tetrahydrofuran is added a solu-tion of 550 m~ of thiourea in 20 m~ of ethanol, followed by addition of 50 mg of triethylbenzylammonium bromide.
r~he mixture is stirred for 2() hours at room temperature and concentrated. r~he residue is dissolved in a ~ixture of ethyl acetate and tetrahydrofuran and the solution was washed with ag. sodium bicarbonate solution and then water, followed by drying over anhydrous magnesium sulfate. rl'he dried solution is subjected to distillation of the solvent to give powcter which is washed with chloroform and ether and dried. r~he procedl1re ;yield~; 1 0~7 g oî 7~-~a-ethoxy-imino-(2-aminothiazol-4-:sl,acetamido 1-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester. Yield 52 9 %.
~MR(ppm, 60MHz, CDG~ d6-DMS0(3:1~): 1.38(3H,t,C~CH2-), 3.78(2H,broad S, 2-CH~,), 3.90(3H~S,N-CH3), 4.30(2H, broad S, 3-CH2), 4.38i2H~q~GH3cH2)~ 5 ~ , 6.00~1H,d,7-H~, 6~88~1H,S,CHPh2), 7~20-7.60(10H,m,Ph2), 7.48~1H,S,thiazole ring proton) ~23l6~
~ o a solution of 750 mg of 7~ ethoxyimino-(2-aminothi~zol-~-yl)ace-tamido)-3-(1-methyl-lH-te-trazol~5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester in 10 m~ of 90 % formic acid is added 654 mg of zinc dust, cooling to -10C. After the mixture is stirred for 20 minutes at -10C and further for 10 ~inutes at room tempera-ture, the insoluble materials is filtered off. The filtrate is neutralized with aq. sodium bicarbonate solution and extracted with ethyl acetateO The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate, after which time the solvent is distilled off to give 465 mg of foamy materials, All of the foamy materials are dissolved in a mixture of 2 ~R of trifluoroacetic acid and 0.5 m~ of anisole, stirred for 30 minutes under ice-cooling and then for ~ minutes at room temperature, Thus obtained solution is concentrated, and to the residue is poured ether to precipitate a solid. The solid is washed twice with ether and dried to obtain ~20 mg of solid product~
This solid product is dissolved in an excess amount of aq, sodium bicarbonate solution alld purified with a column of Amberlite XAD-2, The fractions eluted with water is lyophilized to obtain sodium 7~ 2-aminothiazol-4-yl)-glycylamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-~-cephem-4-carboxylate, ~lhiS product is identical with the compound obtained in Example 47 in all respects, ~xample 51 ~o a solution of 18,7 g of ethyl ~-ethoxyimino-~-~Z:~6Z`8~
o~obutyrate in 100 m~ of chloroform gradually is dropwise added a solution of 1~ 9 g of bromine in 20 m~ o~ chloroform under ice-cooling. The solution is stirred for ~0 minutes at the same tempera-ture and further for 1 0 5 hours a-t room temperature The reaction mixture is washed with water, aq sodium bicarbonate solution and then water in -this order, followed by drying over anhydrous magnesium sulfate.
The dried solution is subjected to the evaporation of the solvent, and to the residue is added 25C m~ of ethanol and 15 2 g of thiourea. Thus miYture is refluxed for 2 hours and cooled, followed by the distillation o~ the solvent under reduced pressure To the residue is added 250 m~ of water to precipitate a solid which is collected by means of filtration and washed with water and dried. The procedure gives 17.9 g of ethyl a-ethoxyimino-2-aminothiazol-4-yl-acetate hydrobromide Yield 55 ,~.
Analysis - Calcd. for C9Hl4~2035Br:
C, 3Z 34j H, 4 351 N, 12.~
Found C, 32.52; H, 3.~j N, 12 92 NMR(ppm, lOOMHz, d~-DM~0): 1020 and 1 32 ~6H,two t, CH~CH~) t 23 and ~I.37~4~l, tWQ q, CH3CH2), 7 63(1H,S, thiazole ring proton), 9.12(2H, broad S, NH2 Example ~2 To a solu-tion of 2 43 g of ethyl a-ethoxyimino-2-aminothiazol-4-ylacetate hydro~romide in 25 m~ of anhydrous N,N-dimethylacetami(le is added 1 43 g of chloroacetyl chloride under cooling and stirring. The solution is stirred for 30 minutes under ice-cooling and then for 30 minutes at 6Z8~
room temperature. To the reaction mixture is added 150 mk of ethyl aceta-te and the mixture is re~peatedly washed with saturated aq. NaC~ solution, The ethyl acetate layer is dried over anhydrous magnesium sulfate, and subjected to the distillation of the solverlt under reduced pressureO To the residue is added water to precipitate solid material, '~he solid is collected by filtration and driedO The procedure gives 1,90 g of ethyl a-ethoxyimino-2-~chloroacetamino)-thiazol-4-ylacetate, Yield 79 ~
~M~(ppm, lOGMHz, d6-DMS0): 1.24 and 1,27 l6H, two t, CH CH2), 4,22(4H1 two q, Gn3CH2), 4.30(2H,S,C~CH2C0), 7 . 99 (lH,S, thiazole ring proton), Example 5~
1,06 g of ethyl a-ethoxyimino-2-(chloroacetylamino)-thiazol-4-ylacetate is suspended in a solution of 0,9LL g of potassium hydroxide in a mixture of 40 m~ of ethanol and 2 m~ of wa-ter and the suspension is stirred at room tempera-ture to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduc~d pressure and the residue is adjusted to pH 2,0 with lN hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried, The procedure yields 0.88 g of a-ethoxyimino-2-(chloroacetyl~mino)thiazol-L~-ylacetic acidO Yield 91 /0.
Analysis - Calcd. for C9HloN304$C~:
C, 3r~.05; H, 3045., N~ 1'L.41O
~ound . C, 37.17; H, 3.4L~; N~ .09 lZ~ÇjZ84 NMR(ppm, lOOMHz, d6-DM~Oj: 1028(~H,t,C ~ CrI2), 4 22(2H,q, CH3CH2), 4.32(2H,S,C~CH~C~), 8 OO(lH~,thiazole ring -proton) E~ample 54 (1) 'rO a solution of 5 03 ~ of N-~ -trichloroethoxy-carbonyl)thiourea and 5 32 g of ethyl a-ethoxyimino-B-oxo-Y-bromobutyrate in 50 m~ of ethanol is added 300Z g of N,~-dimethylaniline and the mixture is heated for 2 hours in water bath of 80C The reaction solution is subjected to the distilla-tion of ethanol and the residue is dissolved in ethyl acetate ~he ethyl acetat-e solution is washed with dilute hydrochloric acid and then ~ater, and dried, followed by the distillation of the solvent to give 70~5 g of ethyl ~-(2-B,~,~-trichlcroethoxycarbonylaminothiazol-~-yl)-a-ethoxyiminoacetate as an oilO
~2) To a solution of 2.00 g of ethyl a-(2~ -trichloro-ethoxycarbonylaminothiazol-4-yl)-~-ethoxyiminoacetate in 40 m~ of methanol is added 20 me of lN sodium hydroxide The solution is stirred for 2 hours at 50C and concentrated ~o the concentrate is added 50 m~ of water and thus obtained solution is ~ashed -twice with ethyl ace-tate Aqueous layer is adjusted to pH ~ 0 with 3N hydrochloric acid to separa-te white solid. ~he white solid is filtered, washed with water and dried to give 1 40 g of a-etho~yimino-2-(~ -tri-chloroetho~ycarbonylamino)thiazol-4-ylacetic acid Yield 74 . 9 fi o ~Z~L6Z84 Analysis - Calcd. for CloHloNzO5$C~3:
C, 30.75, H, 2.5~; N, 10.76 ~ ound C, Z0087; H, 2.41; N, 10 66 NMR(ppm, 60MHz, d~-DMS0)~ 3H,t,C ~ CH2), 4 06(2H,q, ~I3CH~), 4 90(2H,~,C~3CCH2o), 7.40(1H,S~-thiazole ring proton) Example 55 To a suspension of 6~0 g of 7a-methoxy-7~-c~mino-3-desacetoxycephalosporanic acid t-butyl ester in 180 m~ of N,N-dimethylacetamide is added under stirring ~ 25 g of powdered 2~ -trichloroethoxycarbonylamino)thiazol-4-yl-~-hydroxyacetic acid cyclic carboxyanhydride and then further stirrcd for one hour The reaction mixture is shaken well with 500 m~ of ethyl acetate and the organic layer is washed with water, 5 % sodium bicarbonate aqO
solution and saturated aq. NaGR solution in this order, followed by drying over anhydrous magnesium sulfate ~he ethyl acetate layer is subjected to the distillation of e-thyl acetate to give 1002 g of ~rude 7~-methoxy-7B-i2-~ trichloroethoxy(arbonyl~mino)thiazol-4-yl-a-hydroxy-acetamido~-3-desacetoxycephalosporanic acid t-bu-tyl ester as an oil. ~o a solution of this oily product in 400 m~
of 90 ,' formic acid is added 10 g of zinc dust under cooling and stirring and the mixture is reacted for 2 hours. After insoluble materials are filtered off, the fil-trate is added to 200 m~ of saturated NaC~ aq. solution~ and the resultant solution is extracted with ethyl acetate~ The ethyl acetate layer is washed with water and dried, followed by the distil-~Zl~Z~
la-tion of ethvl ace-tate to ob-tain 5 3 g of crude 7a-methoxy-7~-i(2-aminothiaæol-4-yl)-a-hydroxyacetamido)-3-desace-toxy-cephalosporanic acid t-butyl ester as an oil ~ 'his oily product is added to a mixture of 25 mR of trifluoroacetic acid and 25 mR of anisole under ice-cooling, and the mixture is stirred for 30 minutes under the same condition. ~o the reaction mixture is poured 200 mR of absolute ether, and resulting precipitates are collected by means of filtration. ~he precipitates are dissolved in ~0 mil of 5 % sodium bicarbonate aq. solution~ and thus obtained solution is ~assed through a column of Amberlite XAD-2, followed by elution with water The procedure yields 525 mg of sodium 7~-methoxy-7~ 2-aminothiazol-~-yl)-a-hydro~yacetamicloi-3-desacetoxycephalosporanate as a powderO
Analysis - Calcd. for C14H1506N~2Na 2 C, 36.67; H, 4 17; N, 12022 ~ ound C, 36 23 5 H, 4.38; N, 11 97 NMR(ppm, lOOMHz, CF~COOD): 2 15~3H,S,3-CH3) 9 3 45(3H,~, 7-OCH3), 6 25(1H,~,thiazole ring proton)~
Example 56 '~o a solution of 2703 g of ethyl ~-methoxyimino-~-oxobutyrate in 120 mR of chloroform is dropwise added a solution of 25 3 g of bromine in 30 mR of chloroform over a period of 30 minutes. The solution is stirr~d for 1 hour at room temperature, and washed with dilute sodium bicarbonate aq. solution and water and dried. The dried solution is subjected to the distillation of the solvent to give an oily ~rude product of ethyl a-metho~yimino-~-~Zl~Z84 oxo-y-bromobutyrate. ~he crude product is dissolved in 250 m~ of ethanol and 24 g of thiourea is added thereto, followed by refluxing for ~ hours. After cooling, the precipitates are collected by filtration, -,rashed with etha~ol and then suspended in 300 m~ of a mixture of ethyl acetate and tetrahydrofuran (1:1) To -the suspension is added -to 200 m~ of 10 ~/c sodium bicarbonate aq solution and the mixture is thoroughly shaken. The organic layer is dried and subjected to the distillation of the solvent to give crystal, followed by washing with ether. The procedure gives 16.86 g of ethyl a-methoxyimino-a-(2-aminothiazol --4-yl)acetate Melting point: 112 - 113C
Analysis - Galcd. for C8HllN303S:
C, 41.91; ~, 4 ~4 ~ound : C, 41~20; H, 4 70 ~M~ppm, 60MHz,CDC~3): 4~04(~H,S, OCH3), 7.44~1H,S, thiazole ring proton) ~ mple 57 To a solution of 10 g of ethyl a-methoxyimino-a-~2-aminothiazol-l~-yl)acetate in 100 m~ of dimethylacetamide is dropwise added 5 91 g of chloroac:etyl chloride under ice-cooling. After the stirring for 1 hour at room tempera-ture, the reaction mix-ture is poured into ice-water and the resultant solution is extracted with ethyl acetateO The organic layer is washed and dried, followed by the distilla-tion of solvent to give 12066 g of ethvl ~-methoxyimino-c~-l2-(chloroacetc~mido)thiazol-4-yl)acetate as a crystal Melting point: 81-82C
~Z~284 Analysis - CalcdO for CloHl~N304SC~:
C, 39 29j H~ 3.95 Found : C, 38 74j H, 3 58 NI~R(ppm, 50MHz, CDCR~): 4.10(3H,S,OCH3), 4o24(2H~s7cRcH2co-) 7.9~'(1H,S,thiazole ring proton) ~xample 58 12.66 g of ethyl a-methoxyimino-a-(2-(chloroacetamido)-thiazol-4-yl)acetate is added to a solution of 11074 g of potassium hydroxide in a mixture of 25 mR of water and 500 mR of ethanol After stirring for 20 minutes at room temperature, the reaction solution is subjected -to the distillation of ethanol under reduced pressureO ~he residue is added to water, and the resultant solution is made acidic with addition of i~-hydrochloric acid, followed by separating the insoluble materials by filtration The procedure yields 10 54 g of a-metho~yimino-a-l2-(chloro-acetamido)thiazol-4-yl)acetate Mel-ting point: 18~-183Co Analysis - Calcd. for C8H8N304SCk:
C, Z4160; Hg ~.90; N, 15~1~
Found : C, ~/~ 5~; H, ~.00; N, 14.80 NM~(ppm, 60MHz, d6-DMSO): 4.00(3H,S,OCH3), 4~38(2H,S, CRCH2CO), 8.00(1H,S, thiazole ring proton) Example 59 ~ o a suspension of 555 4 mg of a-methoxyimino-~-i2-~chloroacetamido)thiazol-4-yl)acet-ic acid in 5 m~ of methylene chloride is added 416 Z mg of phosphorus penta-chloride under ice-coolingO The resultant solution is stirred for 30 minu-tes, and n-hexane is added thereto to .
2~
precipitate 620 mg of a-methoxyimino~ 2-~chloroace-tamido)-thiazol-4-yl~acetyl chloride hydrochloric acid salt, Analysis - Calcd, for C8H7N~03SC~-EC~ :
C, 28089; H, 2042j N, 12,63 Found : C, ~8,35j H, 2.81; N, 12.00 5.26 g of the above-mentioned salt is added under ice-cooling to a solution of 2.~6 g of pyridine and 4 g of 7-aminocephalosporanic acid t-bu-tyl ester in 60 m~ of metl~ylene chloride, After the stirring for 1 hour at room temperature, 60 m~ of chloroform is added to -the reaction mi~ture and the resul-tant solution is washed twice ~ith 0,5N hydrochloric acid and then with water, After drying, the solution is subjected to the distilla-tion to obtain 5 g o~ ~ihi-te powder of 7,B- ~a~methoxy-imino-~-(2-~chloroace-tamido)thiazol-4-yl)acetamido ~ -cephalosporanic acid t-butyl ester, Melting point:
126-127C, Analysis - Calcd. for C22H26N508S3C~:
C, 44,93; ~, 4,4~j ~, 11,91 Found : C, 4L~,74 j H, ~ 4; N, 11,61 NMR~ppm, 60 MHz, CDCR~)^ 1,50(qH,S, t-C4H~) 9 2,10~3H,S, CH~CO), ~,10~3H,S,OCH~), 4,28(2H,S,C~CH2CO), 7,84 (lH,S, thiazole ring proton).
~xam~le 60 5 g of 7~ -metho~yimino-~-~2-~chloroacetamido)-thiazol-4-yl)ace-tamido~cephalosporanic acid -t-butyl ester obtained in EXample 59, 970.5 mg of thiourea and 250 mg.
of triethylbenzylammonium bromide are dissolved in a 8~
mixture of 25 m~ of ethanol and 500 m~ of tetrahydrofuran The solution is stirred at room tempera-ture through a night. The reaction mi~ture is poured into lGO mR of 10 /0 sodium bicarbonate aq. solution and extracted with ethyl acetate~ ~he e-thyl acetate layer is separated and concent-rated ~he oily concentrate is subjec-ted to column chromato-graphy packed with silica gel to obtain 2.23 g of 7~-la-methoYyimino~ 2-c~minothiazol-~-yl)acetamido)cephalos-poranic acid t-butyl ester as a powder.
NMR(ppm, 60M~z, CDCR3): 1.54(~H,S,-t-C4Hg)~ 2~08(3H,S, CH3CO)~ 4-12~3Hts,oCH3), 7.45(1H,S,thiazole ring proton).
'This powder is dissolved in a mi~ture of 1 6 m~ of anisole and 16 m~ of trifluoroacetic acid and the solution is stirred for 2 hours at room temperature, follo~Ted by the addition of 200 m~ of a mixture of ether and hexane (10:1) to precipitate 7~-la-methoxyimino-~-~2-aminothiazol-4-yl)-acetamidolcephalosporanic acid trifluoroacetic acid salt which is collected by filtration and washed with ether Yield 1~5 g~
NM~(ppm, 60 MHz, CF3COOH): 1 ~5(3H,S,CH3CO), 4.00(3H,S, OCH3), 7.74(1H,s~thiazole ring proton).
~xam~le _61 A solution of 450 mg of 7~ methoxyimino-~-(2-aminothiazol 4-yl)acetamido)cephalosporanic acid trifluoro-acetic acid salt and 170 mg of sodium bicarbonate in 5 m~
of water is passed through a column of Amberlite XAD-2 and eluted with water ~he procedure yields 141 mg of sodium 2~3~
7~-(a-methoxyimino-a-(2-aminothi~zol-4-yl)acetamidol-cephalosporanate~ Melting point: 162-163C(dec.).
Analysis - Calcd. for C16H16N507S2N 2 C, 37 43; H, 3.93; ~, 13.64 Found : C, 37.10; H, 4.13; N, 13.34 ~MR(ppm, lOOMHz, D20): 2.17(3H,S, CH3CO), 4.13~3H,S, OCH3), 7.58(1H,,thiazole ring proton).
Example 62 7~ a-methoxyimino-a-(2-aminothiazol-4-yl)acetamidol-cephalosporanic acid trifluoroacetic acid salt is dissolved in a solution of 27? mg of l-methyl-~-mercapto-lH-tetrazole, 555 mg. of sodium bicarbonate and 68 mg of triethylbenzyl-ammonium bromide in 10 m~ of water. The solution is heated at 60C in nitrogen atmosphere for 6 hours. A~ter cooling, the re~ction solution is passed through a column of ~mberlite XAD-2 and eluted with water and then with 2.5 % ethanol. The procedure yields sodium 7~-(a-methoxy-imino-a-~2-aminothiazol-4-yl)acetamodol-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. Melting point: 174-175C(de(.).
Analysis - C~lcd. for C16Hl~N,~ 5 3 2 C, 33.74; H7 3 54; N, 22.1~
Found : C, 34.25; H, 3.81; N, 21.69 NMR(ppm, lOOMHz, D20): 4.10(3H,~,N-CH3), 4.14(3H,S,OCH3), 7.58~1H,S~thiazole ring proton).
The above-mentioned procedure gives a small amount of sodium 7~-(a-methoxyimino-a-(2-aminothiazol-4-yl)-acetamodo~-3-desacetylcephalosporanate as a by-product.
~2:162E~4 Melting poin-t: 195-19~C(decO).
Analysis - Calcd. for C14HlL~506S2 3 2 C, 3403~; H, 4,11; N, lLL.30 ~'ound : C, ~,43; H, 4013; ~, 13,14 NMR(ppm, 60MHz, D20): 4~04(3HtS, OCH3), 7,46(1H~,thiaæole ring proton), 3,52(2H,q,2-CH~), Exam~le 63 To a suspension of 3,4 g of 7-amino-Z,-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 25 m~ of dimethylacetamide is added 2,0 g of a-methoxy-imino-a-l2-~chloroacetamido)thiaæol-4-yl)acetyl chloride hydrochloric acid salt under stirring. After the further stirring for 12 hours at room temperature~ the reaction mixture is poured into water and extracted with ethyl acetate, ~he ethyl acetate extract is washe~ with water and dried and subjected to the distillation of the solvent. ~o the residue is added ethyl acetate and insoluble ma-teri~1s are filtered off. ~he filtrate is contentrated under reduced pressure to obtain crude product 1.114 g of 7~ -methoxy--lmino-a ~-(chloroacetamido)thiazol-4-yl~acetamido ¦ ~Z-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as an oil. ~he oily product is dissolved in 20 mR of a mixture of ethanol and tetrahydrofuran ~1:1) and to the solution is added 4ZO mg of thiourea, followed by stirring for 15 hours at room temperature, The reaction solution is concentrated to dryness under reduced pressure and to the residue is added 10 m~ of water, follo~Ted by stirring to precipitate insoluble materials. The insoluble materials ~2~28~
is collected by filtration and dissolved in 10 /c sodium bicarbonate ag. solution, ~he solution is passed through a column of Amber]ite XAD-2, and eluted with water and then with 2.~ ethanol to obtain sodium 7~ -methoxyimino-~-(2-aminothiazol-4-yl)acetamido)-3-~1-methyl-lH-te-trazol-5-ylthiomethyl)-~-cephem-4-carboxylate" This product is identical with the compound obtaineA in Example 62 in all respects, E~c~-ple 6~
A solution o~ ~0.45 ~ of ~-etho~yimino-~ [2-(tri-chloroethoxycarbonyl~mino)thiazol-~-yl]acetic acid ethyl ester in a mixture of 10 % hydrochloric acid and ethanol is catalytic-hydrogenated over 8.0 g of 5 ~
palladium on charco~l at room temperature under atomos-pheric pressure, After the absorption of two equivalents of hydrogen, the catalyst in the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure, By -the procedure, 7~43 g of a-amino-~-l2-~trichloroethoxycarbonylamino)-thiazol-L~-yl)-acetic acid ethyl ester hydrochloric acid salt is obtained ~yield, 72 ~), This product is suspended in ethyl acetate and the obtained suspension is washed with saturated sodium bicarbonate aq. solution, washed with water and dried over anhydrous ma~nesium sulfate, The oily product obtained by the distillation of the solvent, is dissolved in 60 m~ of N,N-dimethylformamide and, to the solu-tion is added 4,2 g of tetramethylguanidine and then 3,94 g of t-butyloxy-carbonylazide, followed by the stirring for 15 hours at room temperature, ~he reaction mixture is poured into water and ex-tracted with ethyl acetate. ~he organiG layer is washed wi-th lN hydrochloric acid and then saturated NaC~
aq~ solution and dried over anhydrous magnesium sulfate.
The oily product ob-tained by the distillation of the solvent is purified by a column chromatography packed with silica gel. '~he procedure gives 4 06 g of a-t-butyloxy-carbonylamino-a-12-(trichloroethcxycarbonylamino)thiazol-4-yllacetic acid ethyl ester (yield, 46.5 /). Melting point:
94-~50C
Analysis - Calcd. for Cl5H20N306SC~3:
C, 37O79, H, 4.23; N, 8.81 Found : C, 37.64; H, 4 28; N, 8.73 Example 65 '~o a solution of 2 80 g of a-t-butyloxycarbonylamino-a-~2-(trichloroethoxycarbonylamino)thiazol-4-yl)acetic acid ethyl ester in 60 mR of 90 /c formic acid is added 2U80 g of zinc dust under cooling and stirring. The mixture is stirred for 1 hour and zin( dust is filtered off. The filtrate is poured into water and the resul-tant solution is extracte~ with e-thyl ac~ta-te. ~'he organic lay~r is washed with saturated sodium bicarbona-te aq solution and then water, and dried over anhydrous magnesium sulfate.
The distillation of the solvent gives 1026 g (yield, 71 2 /0) of a-t-bu-tyloxycarbonylamino-a-(2-aminothiazol-4-yi)acetic acid ethyl ester as crystalsO Melting point: 143-144C.
Analysis - Calcd. for Cl~HlgN304S:
C, 47.83; H, 6.35; N, 13.95 Fo~d : C, 47.79; H, 6 27; N, 13.70 6Z8~
Example 6~
To a solution of 1,26 g of a-t-butyloxycarbonylamino-a-~2-aminothiazol-4-yl)acetic acid ethyl ester in 5 m~ of N,N-dim~thylacet~mide is added 708 mg of chloroacetyl chloride under stirring, After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate, The organic layer is washed with saturated sodi~ bicarbonate aq, solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1,4~5 g of a-t-butyloxycarbonylamino-a-~2-(chloroacetamido)-thiazol-4-yl~acetic acid ethyl ester as crystals (yield, 90.8 ',!). Melting poin-t. 19~-19~C.
~nalysis - ~alcd. for C14H20C~N305S :
C, 44050; H,5024; N, 11.12 ~ ound : C, 44,87; H95,55; N, 10.94 Example 67 To a solution of 920 mg of a--t-butyloxycarbonylamino-a-l2-(chloroacetamido)thiazol-4-yl)acètic acid ethyl ester in 20 m~ of ethanol i5 added 1.4 m.~ of aqueous solution containing 681 mg of potassium hydroxide and the mixture is stirred for 15 minutes at room temperatureO The reac-tion solution is concentra-ted to dryness under reduced pressure and the residue is dissolved in water, The aqueous solution is adjusted to pH ~.0 with lN hydrochloric acid and ex-tracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, The solvent is distilled -t~ obtain 690 mg of ~-7~
2~3~
t-butyl.oxycarbonylc~mino--a-(2-~chloroacetamino)thiazol-4-yllacetic acid as crystals (yield, 81 O/G) D Melting point:
169-170C(dec.).
Analysis - Calcd. for C12H16C~1~3U5S :
C, 41.21j H, 4,61; N, 12.01 Found : C, 41.40j H, 4,68; N, 11.74 ~xample 68 r~O a suspension of 349 mg of a-t-butyloxycarbonyl-amino-a-~2-~chloroacetamido)thiazol-4-yl)acetic acid in 5 m~ of methylene chloride is added 249 mg of phosphorous pentachloride, and the mixture is stirred at room tempera-ture, ~he mixture is added dropwise under stirring to the solution of 4'~L mg of 7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dissolved in 5 m~ of methylene chloride, followed by the addition of 474 mg of pyridine, After that9the stirring is continued for further 1 hour at room temperature, q`he reaction solution is washed with 0,5N hydrochloric acid and then with w~ter, aIld dried, q'he oily product obtained by the distillation of the solvent is purified by a column chromatography packed wi-th silica gel. r~he procedure gives 513 mg of 7~-~ a-t-butyloxycarbonylamino-a-l~-(chloroacetamido)thiazol~-yllacetamido I -3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-Z-cephem-4-carbox~lic acid diphenylmethyl ester.
I'o a solution of 4~7 mg of this product in 40 m~
of a mixture of -tetrahydrofuran and ethanol (1:1) is added 152 mg of thiourea, and the mixture is stirred for 1,-, hours at room temperature7 ~e reaction solution is condensed under reduced pressure c~nd the presidue is dissolved in ethyl acetate. ~he ethyl acetate solution is washed with water and then driedv ~he oily product obtained by the distillation of the solvent is dissolved in 5 m~ of a mixture of trifluoroacetic acid and anisole (10:1), and the solution is stirred for 2 hours at room tempera-ture, followed by pouring into 50 m~ of ether to preci-pitate a crystalline productO ~'he crystalline product is collected by filtration to give 7~- ~ (2-aminothiazol-4-yl)glycylamido)-3-(1-methyl-1~-tetrazol-5-ylthiomethyl)-~-cephemJI-carboxylic acid trifluoroacetic acid salt~
~his product is dissolved in 5 /~ sodium bicarbonate aq.
solution and the solution is passed through a column of Amberlite XAD-2, followed by the elution with water, ~he procedure gives 103 mg of sodium 7~ 2-aminothiazol-4-yl)glycylamidoi-~-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. This product is identical with the compound obtained in hxample 47 in all respects, Example 6~3 ~ o a solution of` 11 ~ o~` 2-aminothiazol-4-ylglycine ethyl ester in 100 m~ of` dimethylacetamide is added drop-wise 17 g of chloroacetyl chloride for 40 minutes under ice-cooling an~ the mixture is stirred at room temperature over a night. ~`o the reaction mixture is added 200 m~
of ice-water and the mixture is extracted with ethyl acetate. ~he organic layer is washed with water, dried and concentrated to obtain 1408 g o~ 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine ethyl ester as co`lorless ~Z16Z84 crys-tals, Melting point: 102,5-103o5~C~
l~M~ppm, 60MHz,C~C~ 4016~2H,j,CRCH2CO), 4032(2H,S~
C~CH2CO), 5 74(1H~d, -CH~COOH), 7014~1H,~,thiazole ring proton). NH
_ample 70 To a solution of 3054 g of 2-chloroacetamidothiazol-4-yl N-chloroace-tylglycine ethyl ester in 30 m~ of ethanol is added dropwise a solution of 1068 g of potassium hydro-xide in 15 mR of water under ice-cooling, follo~ed by the stirring for 15 minutes. ~thanol is distilled under reduced pressure and the residue is made acidic with 10 % hydro-chloric a(id, followed by the extraction with ethyl acetate.
The ethyl aceta-te layer is washed with watcr and dried.
The distillation of ethyl acetate gives 2,38 g of 2-chloroacetamidothiazol-4-yl ~-chloro~cetylglycine as colorless crystals, Melting point. 1~-186C.
NM~(ppm, 60MHz, d6-DMSO): 4036~2H,S,C~CH2CO), 4,58~2H,S, C~CH2CO), 5~66(1H,d, -CH-COO), 7,40(1H,S,thiazole ring proton). NH
Ex~mple 71 To a suspension of 752 mg of 2-chloroacetamidothiazol-4-yl N-chloroacetylglyGine iIl 10 m~ of methylene chloride is added 499 mg of phosphorous pentachloride~ The mix-ture is homogenized under stirring at room temperature. The homogenized mixture is added to a suspension of 600 mg of 7~-amino-3~ methyl-lH-tetrazol-5-ylthiomethyl~-Z-cephem-4-carboxylic acid suspended in 10 m~ of dimethylacetamide ~216Z~34 and the resultant mixture is stirred for 5 hours at room temperature, ~he reac-tion mixture is poured into ice-water ancl-the mixture is made acidic ~th 10 ~0 hy~rochloric acid, followed by the extraction with ethyl acetcl-te, After washed with water and dried9 the extract is subjec-ted to distillation to give crude product of 7~((2-chloroacet-amidothiazol-4-yl)-N-chloroacetylglycylamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as an oil. ~he crude product is dissolved in 100 m~ of ethanol and to the solution is added 456 mg of thiourea, followed by stirring for 15 hours at room temperature, Ethanol is distilled off under reduced pressure and the residue is dissolved in 5 ~' sodium bicarbonate aqO solution, which is passed throu~h a column of Amberlite ~AD-2, followed by elution with water to obtain 113 mg of sodium 7~
,aminothiazol-4-yl)glycylamido~-3-~l-methyl-lH-tetra201-5-ylthiomethyl)-3-cephem-4-carbQxylic acid, This product is identical with the compound obtained in Exa~ple 47 in all respects,
C, 32.96; H, 4O~3; ~ 23,06, Found: C~ Z2,94; H, 4,61;
N, 22.22 ~Z~I 34 NM~(ppm, 100 ~-Iz, CF3COOD): 5.25 (lH,s, ,CII-COOH), 6.75 (lH,s,5-H), Violet color with Ninhydrin rea~entO
Example ,~0 __ A solution of 19,3 g,of thiourea an~ 5Zo5 g~of e-thyl ~-oxyimino-~ oxo-y-chlorobu-tyrate in 300 m~Oof ethc~lol is stirred for 3 hours at room temperature, and condensed under reduced pressure. Water ~200 m~.) is added to the residue and the ob~ained aqueous solution is washed twice with ether. To this are added 130 m~of 85 /c aq. formic acid and 150 mR.of ethanol. Under ice-cooling ~7 g.of zinc dust is aclded gradually to this mix-ture and stirred for 3 hours at room temperature.
The filtered reaction mixture is passed through a column packed wi-th ion-exchange resin (Amberlite 1~-120(H)).
The column is washed wi-th water and eluted with 10 Y aq.
ammonia to give purified 2-amino-thia~ol-4-ylglycine (27.5 g.) which is iden-tical with the sc-~ple obtained in hxc~mple ~9 in all respects.
Exc~mple_ 31 Ethyl ~-oxyimino-2-aminothia~;ol-4-ylacetate hydro--chloride (503 mg~ is dissolved in 10 m~Oof 50 O/G aq.formic acid and 5 m~.of ethanol. Zinc dust (300 mg.) is added to -this solution under ice-cooling and stirred for 3 hours.
The reaction mix-ture is condensed under reduced pressure below 30C, and the residue is made pH 7,5 by adding lN-NaOH. Ethyl acetate extraction gives 2-aminothiazol-4-~2~6;~
ylgl-gcine ethyl ester. 130 mg, N~R(ppm, 60 ~iHz, C~zCOOD): 1,0'~3H,-t,-CH2C ~ )~ 4o18( 2H,q~
-CH~CH3), 50Z5(lH 7 S, , CH-C0~2Hr,)~ 6090(lH,s,5-H).
Mass: m/e 201,0549(theoretical: 201,0571) Example ~2 To a solutisn of 26.6 g.of ethyl a-acetamido--,B-oxo-y-bromobutyrate in a mixture of 50 m~Oof ethanol and 20 m~.
of ether are added 9 o 14 g.of thiourea and 15 m~Oof pyridine.
The mixture is stirred for 1 hour at room temperature and then 4 hours under reflux. The reaction mixture is condensed under reduced pressure and 5~ m~.of ethyl aGetate is added to the residue. The mixture is extrac-ted with 3N-HC~, The water layer thus separated is made pH 10 by adding lN-NaOH and extracted with ethyl acetateO
The ethyl aceta-te extract is washed9 driecl and con-densedO To this concentrate is added small ~uantity of chloroform to cause crystallization of ethyl ~-acetamido-2-amino-thiazol-4-ylacetateO 7.0 g. Melting point: 161,1C.
Analysi~ - Calcd. f'or C9H1303N;~S:
C, 44.43; H, 5.39; N, 17.27. Found: C, 44046; H, 5.24;
N, 16.99 xample 33 To a solution of ~406 gOof ethyl ~-acetamido-~-oxo-r-promobutyrate in a mixture of 50 m~Oof ethanol and 20 m~.of ether are added 1809 gOof N-acetylthiourea and 15 m~Oof pyridine. The mixture is heated under reflux for 4 hours, and condensed under reduced pressure, The condensate is extracted with ethyl ace-tate and the extrac-t ~6~8~
is washed with 5 % aq NaHCO~, then with water, and driedO
The oily substance which is ob-tained from the extract by removal of the solven-t is purified by silica gel chromato-~;raphy to giVQ e-thyl a-acetamido-2- acetamidothiazol-L~-ylacetate. 4 46 gO Melting point: 14809-150C.
Analysis - CalcdO for CllH15C4 3 2 C, 45 59j H, 5 39; N, 14.500 Found: C, 45 73;
H, 5.40; N, 14021 _a ple 34 To a solution of 2 51 goO:E N-(~ -trichloroethoxy-caroonyl)thiourea c~nd 2 66 g of e-thyl a--acetamido-~-oxo-~-bromobutyra-te in 50 m~Oof ethanol is added 108 gOof N,N-dimethylaniline. The mixture is stirred for 24 hours a-t room tempera-ture, and condensed under reduced pressureO
The residue is dissolved in 30 m~.chloroform and the solu-tion is washed with 3N-HCR, water, and driedO ~he solid matter which is obtained by removal of chlo:rof`o:Lm is purified by sil:ica gel c~hroma-tography to give e-thyl a-acetamido-2-(~113,~-trichloroethoxycarbonylamino)thiazol-4-ylacetate 1 43 g Melting point: 161 9C
Analysis -- Calcd. for C12H14G5 3 3 2 C, 33.'70; H, 3.54; N, 9 82. Found: C, 33.69;
H, 3.64; N, 10.()6 ~M:~(ppm, 100 MXz, d6-DMSO): 1 15(3H,t,-CH2C~)~ 4.09(2H,g, -CH2CH3), 1.88(3H,s9COCH3), 4 96(2H,s,C~3CCH2), 5042(1H,d, ,CHCOCC2~5), 7.1~(1H,s,5-H) ~2~84 Example _~5 To a suspension of 100 mg of ethyl ~-acetamido-2-(~, ~ trichloroethoxycarbonylamino)thiazol-4 ylacetate in 5 m~ of water is added 2 m~.of lN-NaOH and -the mixture is stirred for 2 hours at room temperature. ~he reaction mixture is washed with ethyl acetate and -the water layer is made pH ~.0 with lN-HC~, and then extracted with ethyl acetate The extract is washed, dried 3 and condensed to give l~-acetyl-2~ trichloroethoxycarbonylamino~-thiazol-~-ylglycine. 65 mg. Melting poiNt: 158 ~C.
Analysis - Calcd. for CloHloO5N3 3 2 C, 30.05; H, 2.77; N, 10.51. ~ound: C9 30 15;
H, 2.52; N, 10.23~
NMR(ppm, 100 MHz, d6-D~I~0): 1.89(3H,s,COCH2), 4o97(2H,s, CRzCCH2), 5.40(1H,d, _CHCOOH), 7.10~1H,s,5-E~).
Example 36 To a solution of 238 mg.of e-thyl a-oximino-~-oxo-~-bromobutyrate in 10 me.of ethanol is ~dded 251 mg.of N-(,~,'3,~3-trichloroetho~ycclrbonyl)thiourea and the mixture is heated under reflux for 6 hours After cooling 3 50 m~Oof chloroform is added and the organic solu-tion is washed with water and dried over anhydrous magnesium sulfateO Evapora-tion of the solvent followed by chromatographic purification on silica gel affords 164 mg of ethyl ~-oximino-~-~2-(~
~--trichloroethox~calbonylamino)thiazol-4-yl)acetate.
Analysis - Calcd for CloHloN305$CR3 C, 30 74; H, 2058; N, 10 75; C~, 27~23 ~ound:
C, 30.95; H, 2.51; N, 10075; C~, 270020 ;Z8~
NM~(ppm, 100 MHz, CDCR3): 1035(ZH,t,C ~ CH2), 40Z6(2H,q, CH3CH2), 4 87(2H7s,C~3CCH2), 7O9LL(lH,s1-thiaæole ring proton).
~ xample 37 A solution of 2.0 gcof ethyl a-oximino-a-(2-(~-3~,C3-trichloroethoxycarbonylamino)thiaæol-4-yl)aceta-te in 50 m~.
of 10 % HC~-e-thanol is hydrogenated o~er 005 g.of 5 y palladium-on charco~l un~er shakingO The reaction stops when 90 m~Oof hydrogen is absorbed Additional 1.5 g of the catalyst is added and 170 m~Oof hydrogen is absorbed.
Insoluble material is filtered off and the filtrate is concentratecl under reduced pressure '~he residue is washed with e-ther, and separated q'he separated solid is dissolved in 5 m~.of water and neutralized with 10 % sodium hydrogen carbonate aq. solution, and then extracted with chloroformO
The extract is w~shed with water, drying over ~nhydrous magnesium sulfate and subjected to the evaporation of the sol~ent. '~he resultant residue is followed by chromato-graphic purifica-tion on silica gel column -to afford 560 mg.
of 2-(~,~3,~3-trichloroethoxycarborlylamino)thiazol-4-ylglycine ethyl ester.
Analysis - Calcd, for CloH12N30L~SC~3 C, 31.89; H, 3.21; N, 11.16 Found: C, 31.91 H, 3.0G; N, 10O63.
~IR(ppm, 100 MHæ, CF3C02D): 1.37(3H,t,CHzCH2), 4 47(2H,q, CH2CH~), 4.98(2H,s,C~3CCH2), 5 82(1H,s,CH), 7 0 74 (lH,s,thiazole ring proton).
- 5 ~
628a~
:Example ~8 ~ o a solution of 3 4U g.of 2~ trichlc>roethoxy-carbonylamino)thiazol-4-ylglycine ethyl es-ter in 50 m~ of chloroform are added gradually 1.2 gOof triethylamine and 2 50 g.of ~,13,~-trichloroethoxycarbonyl chloride under stirring at room temperature. After 30 minutes stirring, 100 m~O of chloroform is added to the mixture and the obtained organic solution is washed with saturatecl NaC~ aq.
solution, lN~hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate. Af-ter the evapo-ration of the solven-t n--he} ane is added to the residue to afford crude product. The crude product is recrystallized from a mixture of li~sroin and n--hexane to give ~ 11 g~ of 2- (,B,~ trichloroethoxycarbonylamino)thiazol-4-yl-N-(B, ~,13-trichloroethoxycarbonyl)glycine ethyl es-ter Yield 82 ~.
Analysis - Calcd. for C13H13N~065 6 C1 28.28; H, 2037; N ~ 7061. Found: C~ 28 39;
H, 2.~8; N, 7.71 N~ (ppm, 100 MHz, CDC~3): 1 21(3H,t,CH~;CH2), 4060~2H,q, CH3CH2), ~ 83 and ~86(~H~two s, C~3CCH2), 5.60~1H,d, CH), 6 98(1H,s,thiazole ring proton)~ 7u38(1H,d,a-NH).
Example 39 ~ o a solution of 3~82 gO of 2-(~ trichloroethoxy-carbonylamino)thiazol-4-yl-N~ -trichloroethoxycarbonyl)-glycine ethyl ester in 150 m~ of ethanol is added a solu-tion of 1.94 gO of potassium hydroxide in 10 m~O of water while stirring at room temperature. After 30 minutes stirring, the solution is concentrated under reduced pressure ~6Z8~
and 50 m~.of water is added to the residueO The aqueous solution is washed with ethyl aceta-te, adjusted to pH 2.0 with l~-hydrochloric acid and extracted twice each with 70 m~.of ethyl acetate. The combined extrac-ts are washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressureO n--Hexane is added to the residue to separate crude materialO The crude material is recrystallized from a mixture of ethyl acetate and ligroin to afford 1.83 g.of 2~ trichloroethoxy-carbonylamino)thiazol-4-yl-N~ -trichloroethoxycarbonyl)-glycine Yield 50 h NMR(ppm, 100 MH~, CDC~3): 40~0(4H,s,C~3CCH2~ 4065(1H,s, 2 NH), 5 4~(1H,broad d, C~), 6 14(1H broad d,a-N~I), 6 95(1H,s thiazole ring proton).
Example 40 To a suspension of Xo46 g.of 2-aminothiazol ~--yl-glycine in 100 m~Oof N,N-dimethylacetamide is added dropwise 12 6~ gOof ~,B,~--trichloroethoxycarbonyl chloride while stirring for 30 minutes at room temperatureO After further 30 minutes stirring, 250 m~Oof ethyl acetate is added to the reaction mixture and -the resulting solution is washed with 70 m~.o~ lN-hydrochloric acid ~he ethyl acetate is separated and extracted 3 times with 50 m~of 3 ~0 ag.
potassium hydroxide solution. The combined aqueous extracts are washed with ethyl acetate, adjusted to pH 200 with 1~-hydrochloric acid and extracted 3 times each with 100 m~ of ~L6~8~
ethyl acetate. The combined extracts are washed wi-th wa-ter, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, n-Hexane is added -to the oily residue to precipita-te c~ude material. Crude material is separated and recrystallized from a mixtllre of ethyl acetate and ligroin to afford 510 mg.of 2-(~9~,3-trichloroethoxy-carbonylamino)thiazol--4-yl N~ -trichloroethoxycarbonyl)-glycine. This product is identical with the compound obtained in Example 39 in all respects.
Example 41 To a suspension of 2.4 g.of 7--~mino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3--cephem-4-carboxylic acid in 20 mR.of dimethylacetamide is added 2,4 g.of ~-hydroxy-2-~ ,,B-trichloroethoxycarbonylamino)thiazol--4-ylacetic acid cyclic carboxy anhydride (obtained by the procedure described in ~xample L~) and the mixture is stirred for 15 houxs at room -temperature, Ethyl acetate (100 mR.) is added to -the reaction mixture and filtered, The filtrate is ex-tracted several times with 5 % aq. NaHC03, The combined extract is adjusted to pH 3.0 with 10 % aq. HC~ and extracted with ethyl ace-tate, The ethyl acetate layer is washed with saturated aq, NaCR and dried, Evaporation of the solvent gives 7~- {~-hydroxy-(2-(~9~ trichloroethoxycarbonyl-amino)thiazol-4-yl)acetamidoJ -3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4 carboxylic acid (1.8 g.) as a jelly which is then dissolved in 100 mR. of 90 /c aqc formic acid under ice cooling. To this solution is added 1,8 gO
of zinc dust and stirred for 1 hour under ice-cooling.
~Z1~2B~
The reaction mixture is filtered and condensed under reduced pressure. Water (100 m~ is added to the condensate and H2S gas is bubbled into the aqueous solution to precipitate zinc sulfide. Zinc sulfide is filtered off and the fil-trate is condensed under reduced pressure and the concentrate is dissolved in 5 % aq. NaHC03 solution and the solution is passed through a column packed ~ith polystyrene resin (Amberlite ~AD-2) to give purified 7B~(a-hydroxy-a-(2--aminothiazol '~-yl)acetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt.
Analysis - CalcdO for C15H1505NgS3 3 2 C, Z2.14; H, 3 78; N, 19.99. Found: C, 32.53;
H, 3.77; N, 19.50.
NMR(ppm, 100 M~lz, D20): 3.71(2H,q,2-CH2), 4.14(3H,s~N-CH~), 5.28(1H,s,~ CH-CO~H)~ 5.22(1H,d,6~H) 7 5 75(1H,d,7-H), 6 84(1H,s,5-H).
xample 42 To a solution of 100 8 mg~of NaHC03 ~nd 127 ~ mg.of 5-mercapto-l~methyl--lH-tetraæole in 10 m~.of water is added 486 mg.of sodium 7~ hydroxy-(2-aminothiazol-4-yl)acet-amido)cephalosporana-te. The mixture is stirred at 55C for 20 hours. After cooling the mixture is passed through a column packed with polystyrene resin (Amberlite XAD-2) to give purified sodium 7~-~a-hydroxy--(2-aminothiazol-4-yl)-acetamido)-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate, which is identical with the sample obtained in ~xample 41 in all respects _ 5~ _ ~2:1iZ8~
Example 43 To a suspension of 781 mg~of a~ethoxyimino-(2-( trichloroethoxycarbonylamino)thiazol 4-yl)acetic acid in 15 m~Oof CH2C~2 is added 625 mgOof phosphorus pen-tachlo-ride. ~he mixture is homogenized by stirrin~ for 10 seconds. After stirring at room -temperature for 1 hour, the solvent is removed under reduced pressure and the residue is dissolved in 10 m~.of acetone, On the other hand 7-amino-3-(1-methyl-lH-tetrazol--5-ylthiomethyl)-3-cephem-4-carboxylic acid (657 mg.~ and ~aHC03 (1.68 ~) are dissolved in a mixture of 20 m~.of water and 10 mæ~of acetone. To this solution while ice-cooling, the foregoing acetone solution is added dropwise in a period of 3Q millutes.
After the dropping, the mixture is stirred at room tempera-ture for 2 hours, and condensed under reduced pressure to remove acetone. The concentrate is washed with ethyl acetate, adjusted to pH 2.0 with lN-HC~ and extracted with ethylacetate, The ethyl acetate e~tract is washed with water, clried over anhydrous magnesium sul~ate and condensed to give 7~ -etho~yimino (2-(~ trichloroethoxycarbonyl-~ino)thiazol-4-yl~acetc~idoJ ~ l-methyl-lH-tetrazQl-5-ylthiomethyl)-3-cephem-4-carboxylic acid. 925 mg. Yield 66,0 %.
NMR(ppm, 100 MHz CF3COOD): 1 50~3H,t,CH~CHz), 4.60(2H,q, -CH2CH3), 3.85(2H~q,2-CH2), 4.12(3H s,~-CH3), 4.98 (2H,s,C~CCH2-), 5 38(1H d,6-H), 6002(1H,q,7-H), 7.91(1H,s,5-H)~
` 1~162~4 Example 44 Sodium 7,B- ~ a-ethoxyimino-(2-(,B,~,~-trichloroethoxy-carbonylamino)-thiazol--4-yl)acetamido~ cephalosporanate (667 mg,) NaHC03 (90 mg.)and 5-mercapto-1-methyl-lH-tetra-zole (120 mg.)are dissolved to 20 m~Oof water, The mix-ture is stirred at 60C for 8 hours and filtered, ~he filtrate is adausted to pH 2,0 with lN-HC~ and the solid is separated.
The separated solid is filtered, washed with water and dried over phosphorus pentachloride under reduced pressure to give 7~ a-ethoxyimino-(2-(,B~,B,,B-trichloroethoxycarbonyl-amino)thiazol-4-yl)acetamidoJ -3-(1-methyl-lH-tetrazol-5--ylthiomethyl)-~-cephem--4-carboxylic acid~ (238 mg.)which is iden-tical with the sample obtained in ~xample 43 in all respects.
-- 5~ -~ ~6Z~34 To a suspension of 2 92 ~ of ~-ethoxyimino-(2-(chloroace-tamido)thiazol-4-yl)acetic acid in 50 m~ of methylene chloride is added 2 Q8 g of phosphorus penta-chloride. ~he mixture is stirred for 2 hours at room temperature, after which time methylene chloride is distilled off and the redisue is dissolved in 30 m~ of acetone The acetone solution is added dropwise under ice-cooling in a period of 15 minutes, to the solution of 3.29 g of 7-amino-3-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxy-lic acid and 804 g of sodium bicarbonate dissolved in a mixture of lO0 m~ of water and 50 m~ of acetone Af-ter the addition has been completed, the obtained solution is stirred at room temperature ~or 2 hours and concentrated under reduced pressure to remove aceto~eO ~he concentrate is washed with ethyl acetate and adjusted -to pH 2.0 with 3N
hydrochloric acid under ice-cooling, followed by ex-tracting with ethyl acetate ~he ethyl acetate layer is washed with water and dried o~er anhydrous magnesium sulfate, followed by distillatlon of the solverlt to give 3 80 g of 7~
ethoxyimino-l2-(chloroacetamidG~thiazol-'~-yl)acetamidoJ -3-(l-methyl-lH-te-trazol-5-ylthiomethyl)-3-cephem '~-carboxylic acid. Yield 63 1 %
NMR(ppm, 60 MHz, d6-DMS0~: 1034~3H,-t,CH~CH2-), 3 56(2H, broad S,2-CH2), 3.~5(3E,S,N-CH3), 4 05~ 50(4H,m, CH3CH2- and 3-CH2), 4.24i2H,S,C~CH2C0), 5~04ilH,d, 6-H), 5.70(1H,d,7-H), 7 82(]H,S, thiazole ring pro-ton).
IR(KBr,cm 1): 1760(~-lactamj, 1035~=N-0-C)o - ~7 -6~8 Example ~L6 To a solution of 3 90 g of sodium 7~ a-ethoxyimino-~2-(chloroacetamido)thiazol-4-yl)acetamido J -3-(1-rnethyl-lH-tetrazol-5-ylthiomethyl)-~-cephem-4-carboxylate in 50 m~
of water is added 1.52 g of thiourea. The mixture is stirred at room temperature for 3 hours and adjusted to pH 2 0 with lN hydrochloric acid. The resulting precipitates are filtered,washed with water and dried to obtain 2.L~0 g of 7~ -ethoxyimino-(2-aminothiazol-4-yl)acetamido1-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Yield 7~.1 ,~.
NMR(ppm, 60MHz,d~-DMS0): 1.26~H,t,GH3CH2~ .84~3H,~, ~ -CH3), ~.90-4 40~H,m,CH~CH2- and 3-CH2), 5.02(1H, d,~-H), 5.70(1H,d,7-H), 7.94~1H,S,thiazole ring proton).
I~(KBr,cm ~ ?70 ~-lactam), 1030(=N-0-C) ~xam~le 47 2.0 g of 7~ -ethoxyimino-~2-aminothiazol ~-yl)-acetamidol-~-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-cclrbo~lic acid is dissolved in 50 m~ o~ 90 ~
f`olmic acid. To the solution is added 2048 g of zinc dust under stirring and cooling at the temperature of -10C, and the mixture is further stirred for 15 minutes. Af-ter the reaction has been completed, the insoluble materials are filtered off. Into the f`iltrate is poured ether to precipitate white solid, which is centrifugally separated and washed three times with ether and dried ~yield; 1o66 g)O
This whi-te solid is dissolved in aq. solution of sodium bicarbonate. The solution is subjected to the purification L6~84 using a column of Amberlite XAD-2 and the fractions eluted with water are lyophilized to obtain sodium 7~-((2-c~mino-thiazol-4-yl)glycylamido)-3-~1-me-thyl-lH-tetrazol-5-yl-thio-methyl)-3-cephem-4-carbox~late.
NMR(ppm, lOOMHz,D20): 3.~4(3H,~,~-CH3), 6.74(1H,S,thiazole ring proton).
IX~Br,cm 1): 1760(~-lactam).
UV(~20, nm): 260(cephem) Example 48 (1) ~o a suspension of 6.25 g of phosphorus pentachloride in '~5 mR of anhydrous methylene chloride coolecl at -10C, is added 20 mR of anhydrous methylene chloride solution containing 2.4 g of pyridine and the mixed solution is stirred for 30 minutes ~o the solution is dropwise added a solution of 9.3 g of 7~-~2-thienylacetamido)-3-~1-methyl-lH-tetrazol-5-ylthiomèthyl)-3-cephem-4-carboxylic acid benz-hydryl ester in 30 mR of anhydrous methylene chloride during 30 minutes under stirring and keeping a-t -2C~ 10C. lhe mixture is further stirred for 2 hours at the sc~ne tempera-ture and then eooled to -30C - -20C, followed by adding dropwise 56 m~ of methanol. ~hus obtained solution is stirred for 30 minutes, keeping the temperature of the solution between -5C and 5C, and 60 mR of water is added dropwise thereto, followed by further stirring for 30 minutes Methylene chloride layer is washed with saturated aq. NaCR solution and concentrated. To the concentrate is added a mixture of water and ethyl acetate under stirring to give 4.746 g of 7-amino-3-~1-methyl-lH-tetrazol-5-ylthio-~ 59 -~LZ~6~8~
methyl)-3-cephem-4-car~oxylic acid benzhydryl ester as a crystal Yield 64.0 /, ~2) To a suspension of 2.05 g of ~-ethoxyimino-~-(2-( chloroacetamido)thiazol-4-yllacetic acid in 50 m~ of methylene chloride is added 1.50 g of phosphorus penta-chloride under cooling. ~he mixture is s-tirred for 2 hours at room temperature and subjected to the distillation of methylene chloride. ~he residue is dissolved in 20 m~
of tetrahydrofuran The tetrahydrofuran solution is dropwise added while stirring to a solution of 2,92 g of 7-amino-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carbo~ylic acid benzhydryl ester dissolved in 50 m~ of absolute methylene chloride, followed by the addition of 2,87 g of pyridine uncler ice-cooling. After the addition has been comple-ted and -the temperature of the reaction solution becomes the same as -the room temperature~ the solution is stirred for 2 hours and then concentrated, The residue is dissolved in a mixture of 100 m~e of e-thyl acetate and a little amount of tetrahydrofuran, ~hus ob-tained solution i5 washed with dilute hydrochloric acid, sodium bicarbonate aq. solution and water in this order, dried over anhydrous magnesi~ sulfate and conceIltrated. The concentrate is puri~ied by means of a column of silica gel, ~he fractions eluted with the mixture of ethyl ace-tate and chloroform (1:1) are concentrated to obtaiIl 2.36 g of 7~ -ethoxy-imino-~2-(chloroacetamido)thiazol-4-yl)acetamido,, -3-~1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid benzhydryl ester. Yield 50 /c.
~ÇiZ8~
NMR~ppm, 60MHz, CDC~ lU34(3H,t,CHj5CH2-), 3 68(2H,broad S,~-CH2), ;~.8o(~H~s~N-cH3), 4.26(2H~SsC~CH~C0), 5.04~1H,d,6-H), 5 92(1H,q,7-H), 6.94~1H,S,-CHPh2), 7.20-7.60(10H,m,Ph2), 7.90(1H,S,-thiazole ring prc-ton), 8.45(1H,d,7-~H).
xample 49 r~O a solution of 2.2 g of 7~- a-etho~yimino-~2-(chloroacetamido)thiazol-4-yl )acetamido -3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benz-hydryl ester in 20 m~ of tetrahydrofuran is added a solu-tion of 550 m~ of thiourea in 20 m~ of ethanol, followed by addition of 50 mg of triethylbenzylammonium bromide.
r~he mixture is stirred for 2() hours at room temperature and concentrated. r~he residue is dissolved in a ~ixture of ethyl acetate and tetrahydrofuran and the solution was washed with ag. sodium bicarbonate solution and then water, followed by drying over anhydrous magnesium sulfate. rl'he dried solution is subjected to distillation of the solvent to give powcter which is washed with chloroform and ether and dried. r~he procedl1re ;yield~; 1 0~7 g oî 7~-~a-ethoxy-imino-(2-aminothiazol-4-:sl,acetamido 1-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester. Yield 52 9 %.
~MR(ppm, 60MHz, CDG~ d6-DMS0(3:1~): 1.38(3H,t,C~CH2-), 3.78(2H,broad S, 2-CH~,), 3.90(3H~S,N-CH3), 4.30(2H, broad S, 3-CH2), 4.38i2H~q~GH3cH2)~ 5 ~ , 6.00~1H,d,7-H~, 6~88~1H,S,CHPh2), 7~20-7.60(10H,m,Ph2), 7.48~1H,S,thiazole ring proton) ~23l6~
~ o a solution of 750 mg of 7~ ethoxyimino-(2-aminothi~zol-~-yl)ace-tamido)-3-(1-methyl-lH-te-trazol~5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester in 10 m~ of 90 % formic acid is added 654 mg of zinc dust, cooling to -10C. After the mixture is stirred for 20 minutes at -10C and further for 10 ~inutes at room tempera-ture, the insoluble materials is filtered off. The filtrate is neutralized with aq. sodium bicarbonate solution and extracted with ethyl acetateO The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate, after which time the solvent is distilled off to give 465 mg of foamy materials, All of the foamy materials are dissolved in a mixture of 2 ~R of trifluoroacetic acid and 0.5 m~ of anisole, stirred for 30 minutes under ice-cooling and then for ~ minutes at room temperature, Thus obtained solution is concentrated, and to the residue is poured ether to precipitate a solid. The solid is washed twice with ether and dried to obtain ~20 mg of solid product~
This solid product is dissolved in an excess amount of aq, sodium bicarbonate solution alld purified with a column of Amberlite XAD-2, The fractions eluted with water is lyophilized to obtain sodium 7~ 2-aminothiazol-4-yl)-glycylamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-~-cephem-4-carboxylate, ~lhiS product is identical with the compound obtained in Example 47 in all respects, ~xample 51 ~o a solution of 18,7 g of ethyl ~-ethoxyimino-~-~Z:~6Z`8~
o~obutyrate in 100 m~ of chloroform gradually is dropwise added a solution of 1~ 9 g of bromine in 20 m~ o~ chloroform under ice-cooling. The solution is stirred for ~0 minutes at the same tempera-ture and further for 1 0 5 hours a-t room temperature The reaction mixture is washed with water, aq sodium bicarbonate solution and then water in -this order, followed by drying over anhydrous magnesium sulfate.
The dried solution is subjected to the evaporation of the solvent, and to the residue is added 25C m~ of ethanol and 15 2 g of thiourea. Thus miYture is refluxed for 2 hours and cooled, followed by the distillation o~ the solvent under reduced pressure To the residue is added 250 m~ of water to precipitate a solid which is collected by means of filtration and washed with water and dried. The procedure gives 17.9 g of ethyl a-ethoxyimino-2-aminothiazol-4-yl-acetate hydrobromide Yield 55 ,~.
Analysis - Calcd. for C9Hl4~2035Br:
C, 3Z 34j H, 4 351 N, 12.~
Found C, 32.52; H, 3.~j N, 12 92 NMR(ppm, lOOMHz, d~-DM~0): 1020 and 1 32 ~6H,two t, CH~CH~) t 23 and ~I.37~4~l, tWQ q, CH3CH2), 7 63(1H,S, thiazole ring proton), 9.12(2H, broad S, NH2 Example ~2 To a solu-tion of 2 43 g of ethyl a-ethoxyimino-2-aminothiazol-4-ylacetate hydro~romide in 25 m~ of anhydrous N,N-dimethylacetami(le is added 1 43 g of chloroacetyl chloride under cooling and stirring. The solution is stirred for 30 minutes under ice-cooling and then for 30 minutes at 6Z8~
room temperature. To the reaction mixture is added 150 mk of ethyl aceta-te and the mixture is re~peatedly washed with saturated aq. NaC~ solution, The ethyl acetate layer is dried over anhydrous magnesium sulfate, and subjected to the distillation of the solverlt under reduced pressureO To the residue is added water to precipitate solid material, '~he solid is collected by filtration and driedO The procedure gives 1,90 g of ethyl a-ethoxyimino-2-~chloroacetamino)-thiazol-4-ylacetate, Yield 79 ~
~M~(ppm, lOGMHz, d6-DMS0): 1.24 and 1,27 l6H, two t, CH CH2), 4,22(4H1 two q, Gn3CH2), 4.30(2H,S,C~CH2C0), 7 . 99 (lH,S, thiazole ring proton), Example 5~
1,06 g of ethyl a-ethoxyimino-2-(chloroacetylamino)-thiazol-4-ylacetate is suspended in a solution of 0,9LL g of potassium hydroxide in a mixture of 40 m~ of ethanol and 2 m~ of wa-ter and the suspension is stirred at room tempera-ture to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduc~d pressure and the residue is adjusted to pH 2,0 with lN hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried, The procedure yields 0.88 g of a-ethoxyimino-2-(chloroacetyl~mino)thiazol-L~-ylacetic acidO Yield 91 /0.
Analysis - Calcd. for C9HloN304$C~:
C, 3r~.05; H, 3045., N~ 1'L.41O
~ound . C, 37.17; H, 3.4L~; N~ .09 lZ~ÇjZ84 NMR(ppm, lOOMHz, d6-DM~Oj: 1028(~H,t,C ~ CrI2), 4 22(2H,q, CH3CH2), 4.32(2H,S,C~CH~C~), 8 OO(lH~,thiazole ring -proton) E~ample 54 (1) 'rO a solution of 5 03 ~ of N-~ -trichloroethoxy-carbonyl)thiourea and 5 32 g of ethyl a-ethoxyimino-B-oxo-Y-bromobutyrate in 50 m~ of ethanol is added 300Z g of N,~-dimethylaniline and the mixture is heated for 2 hours in water bath of 80C The reaction solution is subjected to the distilla-tion of ethanol and the residue is dissolved in ethyl acetate ~he ethyl acetat-e solution is washed with dilute hydrochloric acid and then ~ater, and dried, followed by the distillation of the solvent to give 70~5 g of ethyl ~-(2-B,~,~-trichlcroethoxycarbonylaminothiazol-~-yl)-a-ethoxyiminoacetate as an oilO
~2) To a solution of 2.00 g of ethyl a-(2~ -trichloro-ethoxycarbonylaminothiazol-4-yl)-~-ethoxyiminoacetate in 40 m~ of methanol is added 20 me of lN sodium hydroxide The solution is stirred for 2 hours at 50C and concentrated ~o the concentrate is added 50 m~ of water and thus obtained solution is ~ashed -twice with ethyl ace-tate Aqueous layer is adjusted to pH ~ 0 with 3N hydrochloric acid to separa-te white solid. ~he white solid is filtered, washed with water and dried to give 1 40 g of a-etho~yimino-2-(~ -tri-chloroetho~ycarbonylamino)thiazol-4-ylacetic acid Yield 74 . 9 fi o ~Z~L6Z84 Analysis - Calcd. for CloHloNzO5$C~3:
C, 30.75, H, 2.5~; N, 10.76 ~ ound C, Z0087; H, 2.41; N, 10 66 NMR(ppm, 60MHz, d~-DMS0)~ 3H,t,C ~ CH2), 4 06(2H,q, ~I3CH~), 4 90(2H,~,C~3CCH2o), 7.40(1H,S~-thiazole ring proton) Example 55 To a suspension of 6~0 g of 7a-methoxy-7~-c~mino-3-desacetoxycephalosporanic acid t-butyl ester in 180 m~ of N,N-dimethylacetamide is added under stirring ~ 25 g of powdered 2~ -trichloroethoxycarbonylamino)thiazol-4-yl-~-hydroxyacetic acid cyclic carboxyanhydride and then further stirrcd for one hour The reaction mixture is shaken well with 500 m~ of ethyl acetate and the organic layer is washed with water, 5 % sodium bicarbonate aqO
solution and saturated aq. NaGR solution in this order, followed by drying over anhydrous magnesium sulfate ~he ethyl acetate layer is subjected to the distillation of e-thyl acetate to give 1002 g of ~rude 7~-methoxy-7B-i2-~ trichloroethoxy(arbonyl~mino)thiazol-4-yl-a-hydroxy-acetamido~-3-desacetoxycephalosporanic acid t-bu-tyl ester as an oil. ~o a solution of this oily product in 400 m~
of 90 ,' formic acid is added 10 g of zinc dust under cooling and stirring and the mixture is reacted for 2 hours. After insoluble materials are filtered off, the fil-trate is added to 200 m~ of saturated NaC~ aq. solution~ and the resultant solution is extracted with ethyl acetate~ The ethyl acetate layer is washed with water and dried, followed by the distil-~Zl~Z~
la-tion of ethvl ace-tate to ob-tain 5 3 g of crude 7a-methoxy-7~-i(2-aminothiaæol-4-yl)-a-hydroxyacetamido)-3-desace-toxy-cephalosporanic acid t-butyl ester as an oil ~ 'his oily product is added to a mixture of 25 mR of trifluoroacetic acid and 25 mR of anisole under ice-cooling, and the mixture is stirred for 30 minutes under the same condition. ~o the reaction mixture is poured 200 mR of absolute ether, and resulting precipitates are collected by means of filtration. ~he precipitates are dissolved in ~0 mil of 5 % sodium bicarbonate aq. solution~ and thus obtained solution is ~assed through a column of Amberlite XAD-2, followed by elution with water The procedure yields 525 mg of sodium 7~-methoxy-7~ 2-aminothiazol-~-yl)-a-hydro~yacetamicloi-3-desacetoxycephalosporanate as a powderO
Analysis - Calcd. for C14H1506N~2Na 2 C, 36.67; H, 4 17; N, 12022 ~ ound C, 36 23 5 H, 4.38; N, 11 97 NMR(ppm, lOOMHz, CF~COOD): 2 15~3H,S,3-CH3) 9 3 45(3H,~, 7-OCH3), 6 25(1H,~,thiazole ring proton)~
Example 56 '~o a solution of 2703 g of ethyl ~-methoxyimino-~-oxobutyrate in 120 mR of chloroform is dropwise added a solution of 25 3 g of bromine in 30 mR of chloroform over a period of 30 minutes. The solution is stirr~d for 1 hour at room temperature, and washed with dilute sodium bicarbonate aq. solution and water and dried. The dried solution is subjected to the distillation of the solvent to give an oily ~rude product of ethyl a-metho~yimino-~-~Zl~Z84 oxo-y-bromobutyrate. ~he crude product is dissolved in 250 m~ of ethanol and 24 g of thiourea is added thereto, followed by refluxing for ~ hours. After cooling, the precipitates are collected by filtration, -,rashed with etha~ol and then suspended in 300 m~ of a mixture of ethyl acetate and tetrahydrofuran (1:1) To -the suspension is added -to 200 m~ of 10 ~/c sodium bicarbonate aq solution and the mixture is thoroughly shaken. The organic layer is dried and subjected to the distillation of the solvent to give crystal, followed by washing with ether. The procedure gives 16.86 g of ethyl a-methoxyimino-a-(2-aminothiazol --4-yl)acetate Melting point: 112 - 113C
Analysis - Galcd. for C8HllN303S:
C, 41.91; ~, 4 ~4 ~ound : C, 41~20; H, 4 70 ~M~ppm, 60MHz,CDC~3): 4~04(~H,S, OCH3), 7.44~1H,S, thiazole ring proton) ~ mple 57 To a solution of 10 g of ethyl a-methoxyimino-a-~2-aminothiazol-l~-yl)acetate in 100 m~ of dimethylacetamide is dropwise added 5 91 g of chloroac:etyl chloride under ice-cooling. After the stirring for 1 hour at room tempera-ture, the reaction mix-ture is poured into ice-water and the resultant solution is extracted with ethyl acetateO The organic layer is washed and dried, followed by the distilla-tion of solvent to give 12066 g of ethvl ~-methoxyimino-c~-l2-(chloroacetc~mido)thiazol-4-yl)acetate as a crystal Melting point: 81-82C
~Z~284 Analysis - CalcdO for CloHl~N304SC~:
C, 39 29j H~ 3.95 Found : C, 38 74j H, 3 58 NI~R(ppm, 50MHz, CDCR~): 4.10(3H,S,OCH3), 4o24(2H~s7cRcH2co-) 7.9~'(1H,S,thiazole ring proton) ~xample 58 12.66 g of ethyl a-methoxyimino-a-(2-(chloroacetamido)-thiazol-4-yl)acetate is added to a solution of 11074 g of potassium hydroxide in a mixture of 25 mR of water and 500 mR of ethanol After stirring for 20 minutes at room temperature, the reaction solution is subjected -to the distillation of ethanol under reduced pressureO ~he residue is added to water, and the resultant solution is made acidic with addition of i~-hydrochloric acid, followed by separating the insoluble materials by filtration The procedure yields 10 54 g of a-metho~yimino-a-l2-(chloro-acetamido)thiazol-4-yl)acetate Mel-ting point: 18~-183Co Analysis - Calcd. for C8H8N304SCk:
C, Z4160; Hg ~.90; N, 15~1~
Found : C, ~/~ 5~; H, ~.00; N, 14.80 NM~(ppm, 60MHz, d6-DMSO): 4.00(3H,S,OCH3), 4~38(2H,S, CRCH2CO), 8.00(1H,S, thiazole ring proton) Example 59 ~ o a suspension of 555 4 mg of a-methoxyimino-~-i2-~chloroacetamido)thiazol-4-yl)acet-ic acid in 5 m~ of methylene chloride is added 416 Z mg of phosphorus penta-chloride under ice-coolingO The resultant solution is stirred for 30 minu-tes, and n-hexane is added thereto to .
2~
precipitate 620 mg of a-methoxyimino~ 2-~chloroace-tamido)-thiazol-4-yl~acetyl chloride hydrochloric acid salt, Analysis - Calcd, for C8H7N~03SC~-EC~ :
C, 28089; H, 2042j N, 12,63 Found : C, ~8,35j H, 2.81; N, 12.00 5.26 g of the above-mentioned salt is added under ice-cooling to a solution of 2.~6 g of pyridine and 4 g of 7-aminocephalosporanic acid t-bu-tyl ester in 60 m~ of metl~ylene chloride, After the stirring for 1 hour at room temperature, 60 m~ of chloroform is added to -the reaction mi~ture and the resul-tant solution is washed twice ~ith 0,5N hydrochloric acid and then with water, After drying, the solution is subjected to the distilla-tion to obtain 5 g o~ ~ihi-te powder of 7,B- ~a~methoxy-imino-~-(2-~chloroace-tamido)thiazol-4-yl)acetamido ~ -cephalosporanic acid t-butyl ester, Melting point:
126-127C, Analysis - Calcd. for C22H26N508S3C~:
C, 44,93; ~, 4,4~j ~, 11,91 Found : C, 4L~,74 j H, ~ 4; N, 11,61 NMR~ppm, 60 MHz, CDCR~)^ 1,50(qH,S, t-C4H~) 9 2,10~3H,S, CH~CO), ~,10~3H,S,OCH~), 4,28(2H,S,C~CH2CO), 7,84 (lH,S, thiazole ring proton).
~xam~le 60 5 g of 7~ -metho~yimino-~-~2-~chloroacetamido)-thiazol-4-yl)ace-tamido~cephalosporanic acid -t-butyl ester obtained in EXample 59, 970.5 mg of thiourea and 250 mg.
of triethylbenzylammonium bromide are dissolved in a 8~
mixture of 25 m~ of ethanol and 500 m~ of tetrahydrofuran The solution is stirred at room tempera-ture through a night. The reaction mi~ture is poured into lGO mR of 10 /0 sodium bicarbonate aq. solution and extracted with ethyl acetate~ ~he e-thyl acetate layer is separated and concent-rated ~he oily concentrate is subjec-ted to column chromato-graphy packed with silica gel to obtain 2.23 g of 7~-la-methoYyimino~ 2-c~minothiazol-~-yl)acetamido)cephalos-poranic acid t-butyl ester as a powder.
NMR(ppm, 60M~z, CDCR3): 1.54(~H,S,-t-C4Hg)~ 2~08(3H,S, CH3CO)~ 4-12~3Hts,oCH3), 7.45(1H,S,thiazole ring proton).
'This powder is dissolved in a mi~ture of 1 6 m~ of anisole and 16 m~ of trifluoroacetic acid and the solution is stirred for 2 hours at room temperature, follo~Ted by the addition of 200 m~ of a mixture of ether and hexane (10:1) to precipitate 7~-la-methoxyimino-~-~2-aminothiazol-4-yl)-acetamidolcephalosporanic acid trifluoroacetic acid salt which is collected by filtration and washed with ether Yield 1~5 g~
NM~(ppm, 60 MHz, CF3COOH): 1 ~5(3H,S,CH3CO), 4.00(3H,S, OCH3), 7.74(1H,s~thiazole ring proton).
~xam~le _61 A solution of 450 mg of 7~ methoxyimino-~-(2-aminothiazol 4-yl)acetamido)cephalosporanic acid trifluoro-acetic acid salt and 170 mg of sodium bicarbonate in 5 m~
of water is passed through a column of Amberlite XAD-2 and eluted with water ~he procedure yields 141 mg of sodium 2~3~
7~-(a-methoxyimino-a-(2-aminothi~zol-4-yl)acetamidol-cephalosporanate~ Melting point: 162-163C(dec.).
Analysis - Calcd. for C16H16N507S2N 2 C, 37 43; H, 3.93; ~, 13.64 Found : C, 37.10; H, 4.13; N, 13.34 ~MR(ppm, lOOMHz, D20): 2.17(3H,S, CH3CO), 4.13~3H,S, OCH3), 7.58(1H,,thiazole ring proton).
Example 62 7~ a-methoxyimino-a-(2-aminothiazol-4-yl)acetamidol-cephalosporanic acid trifluoroacetic acid salt is dissolved in a solution of 27? mg of l-methyl-~-mercapto-lH-tetrazole, 555 mg. of sodium bicarbonate and 68 mg of triethylbenzyl-ammonium bromide in 10 m~ of water. The solution is heated at 60C in nitrogen atmosphere for 6 hours. A~ter cooling, the re~ction solution is passed through a column of ~mberlite XAD-2 and eluted with water and then with 2.5 % ethanol. The procedure yields sodium 7~-(a-methoxy-imino-a-~2-aminothiazol-4-yl)acetamodol-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. Melting point: 174-175C(de(.).
Analysis - C~lcd. for C16Hl~N,~ 5 3 2 C, 33.74; H7 3 54; N, 22.1~
Found : C, 34.25; H, 3.81; N, 21.69 NMR(ppm, lOOMHz, D20): 4.10(3H,~,N-CH3), 4.14(3H,S,OCH3), 7.58~1H,S~thiazole ring proton).
The above-mentioned procedure gives a small amount of sodium 7~-(a-methoxyimino-a-(2-aminothiazol-4-yl)-acetamodo~-3-desacetylcephalosporanate as a by-product.
~2:162E~4 Melting poin-t: 195-19~C(decO).
Analysis - Calcd. for C14HlL~506S2 3 2 C, 3403~; H, 4,11; N, lLL.30 ~'ound : C, ~,43; H, 4013; ~, 13,14 NMR(ppm, 60MHz, D20): 4~04(3HtS, OCH3), 7,46(1H~,thiaæole ring proton), 3,52(2H,q,2-CH~), Exam~le 63 To a suspension of 3,4 g of 7-amino-Z,-~l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 25 m~ of dimethylacetamide is added 2,0 g of a-methoxy-imino-a-l2-~chloroacetamido)thiaæol-4-yl)acetyl chloride hydrochloric acid salt under stirring. After the further stirring for 12 hours at room temperature~ the reaction mixture is poured into water and extracted with ethyl acetate, ~he ethyl acetate extract is washe~ with water and dried and subjected to the distillation of the solvent. ~o the residue is added ethyl acetate and insoluble ma-teri~1s are filtered off. ~he filtrate is contentrated under reduced pressure to obtain crude product 1.114 g of 7~ -methoxy--lmino-a ~-(chloroacetamido)thiazol-4-yl~acetamido ¦ ~Z-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as an oil. ~he oily product is dissolved in 20 mR of a mixture of ethanol and tetrahydrofuran ~1:1) and to the solution is added 4ZO mg of thiourea, followed by stirring for 15 hours at room temperature, The reaction solution is concentrated to dryness under reduced pressure and to the residue is added 10 m~ of water, follo~Ted by stirring to precipitate insoluble materials. The insoluble materials ~2~28~
is collected by filtration and dissolved in 10 /c sodium bicarbonate ag. solution, ~he solution is passed through a column of Amber]ite XAD-2, and eluted with water and then with 2.~ ethanol to obtain sodium 7~ -methoxyimino-~-(2-aminothiazol-4-yl)acetamido)-3-~1-methyl-lH-te-trazol-5-ylthiomethyl)-~-cephem-4-carboxylate" This product is identical with the compound obtaineA in Example 62 in all respects, E~c~-ple 6~
A solution o~ ~0.45 ~ of ~-etho~yimino-~ [2-(tri-chloroethoxycarbonyl~mino)thiazol-~-yl]acetic acid ethyl ester in a mixture of 10 % hydrochloric acid and ethanol is catalytic-hydrogenated over 8.0 g of 5 ~
palladium on charco~l at room temperature under atomos-pheric pressure, After the absorption of two equivalents of hydrogen, the catalyst in the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure, By -the procedure, 7~43 g of a-amino-~-l2-~trichloroethoxycarbonylamino)-thiazol-L~-yl)-acetic acid ethyl ester hydrochloric acid salt is obtained ~yield, 72 ~), This product is suspended in ethyl acetate and the obtained suspension is washed with saturated sodium bicarbonate aq. solution, washed with water and dried over anhydrous ma~nesium sulfate, The oily product obtained by the distillation of the solvent, is dissolved in 60 m~ of N,N-dimethylformamide and, to the solu-tion is added 4,2 g of tetramethylguanidine and then 3,94 g of t-butyloxy-carbonylazide, followed by the stirring for 15 hours at room temperature, ~he reaction mixture is poured into water and ex-tracted with ethyl acetate. ~he organiG layer is washed wi-th lN hydrochloric acid and then saturated NaC~
aq~ solution and dried over anhydrous magnesium sulfate.
The oily product ob-tained by the distillation of the solvent is purified by a column chromatography packed with silica gel. '~he procedure gives 4 06 g of a-t-butyloxy-carbonylamino-a-12-(trichloroethcxycarbonylamino)thiazol-4-yllacetic acid ethyl ester (yield, 46.5 /). Melting point:
94-~50C
Analysis - Calcd. for Cl5H20N306SC~3:
C, 37O79, H, 4.23; N, 8.81 Found : C, 37.64; H, 4 28; N, 8.73 Example 65 '~o a solution of 2 80 g of a-t-butyloxycarbonylamino-a-~2-(trichloroethoxycarbonylamino)thiazol-4-yl)acetic acid ethyl ester in 60 mR of 90 /c formic acid is added 2U80 g of zinc dust under cooling and stirring. The mixture is stirred for 1 hour and zin( dust is filtered off. The filtrate is poured into water and the resul-tant solution is extracte~ with e-thyl ac~ta-te. ~'he organic lay~r is washed with saturated sodium bicarbona-te aq solution and then water, and dried over anhydrous magnesium sulfate.
The distillation of the solvent gives 1026 g (yield, 71 2 /0) of a-t-bu-tyloxycarbonylamino-a-(2-aminothiazol-4-yi)acetic acid ethyl ester as crystalsO Melting point: 143-144C.
Analysis - Calcd. for Cl~HlgN304S:
C, 47.83; H, 6.35; N, 13.95 Fo~d : C, 47.79; H, 6 27; N, 13.70 6Z8~
Example 6~
To a solution of 1,26 g of a-t-butyloxycarbonylamino-a-~2-aminothiazol-4-yl)acetic acid ethyl ester in 5 m~ of N,N-dim~thylacet~mide is added 708 mg of chloroacetyl chloride under stirring, After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate, The organic layer is washed with saturated sodi~ bicarbonate aq, solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1,4~5 g of a-t-butyloxycarbonylamino-a-~2-(chloroacetamido)-thiazol-4-yl~acetic acid ethyl ester as crystals (yield, 90.8 ',!). Melting poin-t. 19~-19~C.
~nalysis - ~alcd. for C14H20C~N305S :
C, 44050; H,5024; N, 11.12 ~ ound : C, 44,87; H95,55; N, 10.94 Example 67 To a solution of 920 mg of a--t-butyloxycarbonylamino-a-l2-(chloroacetamido)thiazol-4-yl)acètic acid ethyl ester in 20 m~ of ethanol i5 added 1.4 m.~ of aqueous solution containing 681 mg of potassium hydroxide and the mixture is stirred for 15 minutes at room temperatureO The reac-tion solution is concentra-ted to dryness under reduced pressure and the residue is dissolved in water, The aqueous solution is adjusted to pH ~.0 with lN hydrochloric acid and ex-tracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, The solvent is distilled -t~ obtain 690 mg of ~-7~
2~3~
t-butyl.oxycarbonylc~mino--a-(2-~chloroacetamino)thiazol-4-yllacetic acid as crystals (yield, 81 O/G) D Melting point:
169-170C(dec.).
Analysis - Calcd. for C12H16C~1~3U5S :
C, 41.21j H, 4,61; N, 12.01 Found : C, 41.40j H, 4,68; N, 11.74 ~xample 68 r~O a suspension of 349 mg of a-t-butyloxycarbonyl-amino-a-~2-~chloroacetamido)thiazol-4-yl)acetic acid in 5 m~ of methylene chloride is added 249 mg of phosphorous pentachloride, and the mixture is stirred at room tempera-ture, ~he mixture is added dropwise under stirring to the solution of 4'~L mg of 7~-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dissolved in 5 m~ of methylene chloride, followed by the addition of 474 mg of pyridine, After that9the stirring is continued for further 1 hour at room temperature, q`he reaction solution is washed with 0,5N hydrochloric acid and then with w~ter, aIld dried, q'he oily product obtained by the distillation of the solvent is purified by a column chromatography packed wi-th silica gel. r~he procedure gives 513 mg of 7~-~ a-t-butyloxycarbonylamino-a-l~-(chloroacetamido)thiazol~-yllacetamido I -3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-Z-cephem-4-carbox~lic acid diphenylmethyl ester.
I'o a solution of 4~7 mg of this product in 40 m~
of a mixture of -tetrahydrofuran and ethanol (1:1) is added 152 mg of thiourea, and the mixture is stirred for 1,-, hours at room temperature7 ~e reaction solution is condensed under reduced pressure c~nd the presidue is dissolved in ethyl acetate. ~he ethyl acetate solution is washed with water and then driedv ~he oily product obtained by the distillation of the solvent is dissolved in 5 m~ of a mixture of trifluoroacetic acid and anisole (10:1), and the solution is stirred for 2 hours at room tempera-ture, followed by pouring into 50 m~ of ether to preci-pitate a crystalline productO ~'he crystalline product is collected by filtration to give 7~- ~ (2-aminothiazol-4-yl)glycylamido)-3-(1-methyl-1~-tetrazol-5-ylthiomethyl)-~-cephemJI-carboxylic acid trifluoroacetic acid salt~
~his product is dissolved in 5 /~ sodium bicarbonate aq.
solution and the solution is passed through a column of Amberlite XAD-2, followed by the elution with water, ~he procedure gives 103 mg of sodium 7~ 2-aminothiazol-4-yl)glycylamidoi-~-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. This product is identical with the compound obtained in hxample 47 in all respects, Example 6~3 ~ o a solution of` 11 ~ o~` 2-aminothiazol-4-ylglycine ethyl ester in 100 m~ of` dimethylacetamide is added drop-wise 17 g of chloroacetyl chloride for 40 minutes under ice-cooling an~ the mixture is stirred at room temperature over a night. ~`o the reaction mixture is added 200 m~
of ice-water and the mixture is extracted with ethyl acetate. ~he organic layer is washed with water, dried and concentrated to obtain 1408 g o~ 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine ethyl ester as co`lorless ~Z16Z84 crys-tals, Melting point: 102,5-103o5~C~
l~M~ppm, 60MHz,C~C~ 4016~2H,j,CRCH2CO), 4032(2H,S~
C~CH2CO), 5 74(1H~d, -CH~COOH), 7014~1H,~,thiazole ring proton). NH
_ample 70 To a solution of 3054 g of 2-chloroacetamidothiazol-4-yl N-chloroace-tylglycine ethyl ester in 30 m~ of ethanol is added dropwise a solution of 1068 g of potassium hydro-xide in 15 mR of water under ice-cooling, follo~ed by the stirring for 15 minutes. ~thanol is distilled under reduced pressure and the residue is made acidic with 10 % hydro-chloric a(id, followed by the extraction with ethyl acetate.
The ethyl aceta-te layer is washed with watcr and dried.
The distillation of ethyl acetate gives 2,38 g of 2-chloroacetamidothiazol-4-yl ~-chloro~cetylglycine as colorless crystals, Melting point. 1~-186C.
NM~(ppm, 60MHz, d6-DMSO): 4036~2H,S,C~CH2CO), 4,58~2H,S, C~CH2CO), 5~66(1H,d, -CH-COO), 7,40(1H,S,thiazole ring proton). NH
Ex~mple 71 To a suspension of 752 mg of 2-chloroacetamidothiazol-4-yl N-chloroacetylglyGine iIl 10 m~ of methylene chloride is added 499 mg of phosphorous pentachloride~ The mix-ture is homogenized under stirring at room temperature. The homogenized mixture is added to a suspension of 600 mg of 7~-amino-3~ methyl-lH-tetrazol-5-ylthiomethyl~-Z-cephem-4-carboxylic acid suspended in 10 m~ of dimethylacetamide ~216Z~34 and the resultant mixture is stirred for 5 hours at room temperature, ~he reac-tion mixture is poured into ice-water ancl-the mixture is made acidic ~th 10 ~0 hy~rochloric acid, followed by the extraction with ethyl acetcl-te, After washed with water and dried9 the extract is subjec-ted to distillation to give crude product of 7~((2-chloroacet-amidothiazol-4-yl)-N-chloroacetylglycylamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as an oil. ~he crude product is dissolved in 100 m~ of ethanol and to the solution is added 456 mg of thiourea, followed by stirring for 15 hours at room temperature, Ethanol is distilled off under reduced pressure and the residue is dissolved in 5 ~' sodium bicarbonate aqO solution, which is passed throu~h a column of Amberlite ~AD-2, followed by elution with water to obtain 113 mg of sodium 7~
,aminothiazol-4-yl)glycylamido~-3-~l-methyl-lH-tetra201-5-ylthiomethyl)-3-cephem-4-carbQxylic acid, This product is identical with the compound obtained in Exa~ple 47 in all respects,
Claims (113)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a cephem compound of the formula:
(I) wherein R1 represents amino or hydroxyl; A represents or a group of the fomula >C=NR wherein R5 is hydroxyl or a protected hydroxyl group; R3 represents hydrogen or methoxy;
R15 represents 2-carboxyethenyl, chloro or methoxy group or represents CH2R4; R4 represents i) hydrogen, ii) hydroxyl, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) carbamoyloxy, viii) carbamoylthio, ix) thiocarbamoyloxy, x) any group of ii) to ix) substituted with alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulfonyloxy, xvi) (cis-1,2-epoxypropyl)phosphono or xvii) a group of the formula -S-R wherein R is a 5 or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; and R8 represents hydrogen, or a pharmaceutically acceptable salt or ester thereof, which comprises (1) reacting a compound of the formula:
wherein R3 and R15 are as defined above, or a salt or ester thereof, with a compound of the formula:
wherein R8 is as defined above; R12 represents an amino or hydroxyl group which may be protected; and A' represents any of the radicals as defined for A except that the amino or hydroxyl groups may be protected, or with a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or (2) for preparing a compound of the formula (I) in which A represents , or a pharmaceutically acceptable salt or ester thereof, reducing a compound of the formula:
wherein R3, R5, R8, R12 and R15 are as defined above, or a salt or ester thereof, followed by, if necessary, removal of any protective groups; or (3) for preparing a compound of the formula (I) in which R15 is CH2R4 and R4 is other than acyloxy, carbamoyloxy and hydrogen, or a pharmaceutically acceptable salt or ester thereof, reacting a compound of the formula:
wherein R6 represents an acyloxy, carbamoyloxy or halogen and A', R3, R8 and R12 are as defined above, or a salt or ester thereof, with a tertiary amine or a compound of the formula:
R4'-H wherein R4' represents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammon-ium, followed by, if necessary, removal of any protective groups; and where required converting any free carboxylic acid of the formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or ester of a compound (I) into the free carboxylic acid.
(I) wherein R1 represents amino or hydroxyl; A represents or a group of the fomula >C=NR wherein R5 is hydroxyl or a protected hydroxyl group; R3 represents hydrogen or methoxy;
R15 represents 2-carboxyethenyl, chloro or methoxy group or represents CH2R4; R4 represents i) hydrogen, ii) hydroxyl, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) carbamoyloxy, viii) carbamoylthio, ix) thiocarbamoyloxy, x) any group of ii) to ix) substituted with alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulfonyloxy, xvi) (cis-1,2-epoxypropyl)phosphono or xvii) a group of the formula -S-R wherein R is a 5 or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; and R8 represents hydrogen, or a pharmaceutically acceptable salt or ester thereof, which comprises (1) reacting a compound of the formula:
wherein R3 and R15 are as defined above, or a salt or ester thereof, with a compound of the formula:
wherein R8 is as defined above; R12 represents an amino or hydroxyl group which may be protected; and A' represents any of the radicals as defined for A except that the amino or hydroxyl groups may be protected, or with a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or (2) for preparing a compound of the formula (I) in which A represents , or a pharmaceutically acceptable salt or ester thereof, reducing a compound of the formula:
wherein R3, R5, R8, R12 and R15 are as defined above, or a salt or ester thereof, followed by, if necessary, removal of any protective groups; or (3) for preparing a compound of the formula (I) in which R15 is CH2R4 and R4 is other than acyloxy, carbamoyloxy and hydrogen, or a pharmaceutically acceptable salt or ester thereof, reacting a compound of the formula:
wherein R6 represents an acyloxy, carbamoyloxy or halogen and A', R3, R8 and R12 are as defined above, or a salt or ester thereof, with a tertiary amine or a compound of the formula:
R4'-H wherein R4' represents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammon-ium, followed by, if necessary, removal of any protective groups; and where required converting any free carboxylic acid of the formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or ester of a compound (I) into the free carboxylic acid.
2. A process as claimed in claim 1, wherein starting materials are employed in which A' represents -CH(OH)-.
3. A process as claimed in claim 1, wherein starting materials are employed in which A' represents -CH(NH2)-, or in which starting materials are employed in which A' represents and the resulting imino product is reduced.
4. A process as claimed in claim 1, 2 or 3, wherein starting materials are employed in which R15 represents CH2R4 and R4 represents hydrogen.
5. A process as claimed in claim 1, 2 or 3, wherein starting materials are employed in which R15 represents CH2R4 and R4 represents an acetoxy group.
6. A process as claimed in claim 1, 2 or 3, wherein starting materials are employed in which R15 represents CH2R4 and R4 represents a 1-methyl-1H-tetrazol-5-ylthio group.
7. A process as claimed in claim 1, wherein reaction (1) or (3) is employed, and in the starting materials A' represents a group of the formula wherein R? is a lower alkoxy or a hydroxyl which may be protected by an easily removable protective group, and a compound of the formula (I) in which A is wherein R5 is a lower alkoxy or a hydroxyl is recovered.
8. A process as claimed in claim 1, wherein reaction (1) is employed, and in the starting materials A' represents a group of the formula wherein R? is a lower alkoxy or a hydroxyl which may be protected by an easily removable protective group, and R15 is CH2R4 and R4 is a carbamoyloxy or acyloxy group, and a compound of formula (I) in which A is wherein R5 is a lower alkoxy or a hydroxy and R15 is CH2R4 and R4 is carbamoyloxy or acyloxy is recovered.
9. A process as claimed in claim 7 or 8, wherein the acyloxy group is an acetoxy group.
10. A process according to claim 1, wherein reaction (1) is employed, and in the starting materials R3 represents hydro-gen, R15 represents CH2R4, R4 represents acetoxy, R12 represents a protected amino group and A' represents
11. A process according to Claim 1, wherein reaction (3) is employed, and in the starting materials R3 represents hydrogen, R12 represents amino or a protected amino, A' represents , and wherein said nucleophilic compound is 1-methyl-5-mercapto-1H-tetrazole.
12. A process for the preparation of 7.beta.-[.alpha.-hydroxy-.alpha.-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid and its sodium salt which comprises reacting 7-amino-3-(1-methyl-1H-tetrazol-4-ylthio-methyl)-3-cephem-4-carboxylic acid with .alpha.-hydroxy-.alpha.-[2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid cyclic carboxy anhydride, and removing the protective .beta.,.beta.,.beta.-triethoxy-carbonyl group by reduction with zinc and formic acid, and where required converting the free acid into its sodium salt.
13. A process for the preparation of 7.beta.-[.alpha.-hydroxy-.alpha.-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting 7-aminocephalosporanic acid with .alpha.-hydroxy-.alpha.-[2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid cyclic carboxy anhydride, converting the product into its sodium salt, removing the protective .beta.,.beta.,.beta.-trichloroethoxycarbonyl group by reduction with zinc and formic acid, converting the product into its sodium salt, and reacting the sodium 7.beta.-[.alpha.-hydroxy-.alpha.-(2-aminothiazol-4-yl)acetamido]cephalosporanate with 5-mercapto-1-methyl-1H-tetrazole.
14. A process for preparing 7.beta.-(2-aminothiazol-4-ylglycyl-amido)cephalosporanic acid and its sodium salt which comprises reacting 7-aminocephalosporanic acid with .alpha.-(.beta.,.beta.,.beta.-trichloro-ethoxycarbonylamino)-.alpha.[2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)-thiazol-4-yl]acetyl chloride, converting the product into its sodium salt and removing the protective .beta.,.beta.,.beta.-trichloroethoxy-carbonyl group by reduction with zinc and formic acid, and where required converting the product into its sodium salt.
15. A process for preparing 7.beta.-(2-aminothiazol-4-ylglycylamino)cephalosporanic acid and its sodium salt which comprises reacting .alpha.-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)-.alpha.-[2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)thiazol-4-yl]acetyl chloride with 7-aminocephalosporanic acid, removing the protective .beta.,.beta.,.beta.-trichloroethoxycarbonyl group by reduction with zinc and formic acid, and where required converting the product into its sodium salt.
16. A process for the preparation of 7.beta.-(2-hydroxythiazol-4-ylglycylamido)cephalosporanic acid and its sodium salt which comprises reacting .alpha.-ethoxyimino-.alpha.-(2-hydroxythiazol-4-yl)acetyl chloride with 7-aminocephalosporanic acid, reducing the ethoxyimino group to the amino group by the action of zinc and formic acid, and where required converting the product into its sodium salt.
17. A process for the preparation of 7.alpha.-methoxy-7.beta.-[.alpha.-hydroxy-.alpha.-(2-aminothiazol-4-yl)acetamido]-3-desacetoxycephalos-poranic acid and its sodium salt, which comprises reacting 7.alpha.-methoxy-7.beta.-amino-3-desacetoxycephalosporanic acid or a salt or ester thereof, with .alpha.-[2-(.beta.,.beta.,.beta.-trichloroethoxycarbonylamino)-thiazol-4-yl]-.alpha.-hydroxyacetic acid cyclic carboxyanhydride, removing the protective .beta.,.beta.,.beta.-trichloroethoxycarbonyl group by reduction with zinc and formic acid, and where required converting the product into its sodium salt.
18. A process for the preparation of 7.beta.-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid sodium salt which comprises reacting .alpha.-methoxyimino-.alpha.-[2-(chloroacetamido)-thiazol-4-yl]acetyl chloride with 7-aminocephalosporanic acid or a salt or ester thereof, removing the protective chloroacetyl group by reaction with thiourea to produce 7.beta.-[.alpha.-methoxyimino-.alpha.-(2-aminothiazol-4-yl)-acetamido]cephalosporanic acid and reacting the product with 1-methyl-5-mercapto-1H-tetrazole in the presence of sodium bicarbonate.
19. A process for the preparation of 7.beta.-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl-thio-methyl-3-cephem-4-carboxylic acid and its sodium salt which comprises reacting .alpha.-methoxyimino-.alpha.-[2-(chloroacetamido)-thiazol-4-yl]acetyl chloride with 7-amino-3-(1-methyl-1H-tet-razol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, removing the protective chloroacetyl group by reaction with thiourea, and where required converting the product into its sodium salt.
20. A compound of formula (I) as defined in Claim 1 or a pharmaceutically acceptable salt or ester thereof when prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
21. A process as claimed in Claim 1, wherein reaction (1) is employed and wherein starting materials are employed in which R3 represents methoxy, R4 represents hydrogen, R12 repre-sents a protected amino group and A' represents -CH(OH)- or such a group in which the hydroxyl is protected.
22. A process as claimed in Claim 21, wherein the second starting material of reaction (1), namely, the thiazol-4-yl-acetic acid derivative, is employed in the form of its cyclic carboxyanhydride.
23. A process as claimed in Claim 1, wherein reaction (1) is employed and wherein starting materials are employed in which R3 represents hydrogen, R4 represents 1-methyl-1H-tetra-zol-5-ylthio, R12 represents a protected amino group and A' represents
24. A process as claimed in claim 1, wherein reaction (3) is employed and wherein starting materials are employed in which R3 represents hydrogen, R12 represents a protected amino group, A' represents , and where said nucleophilic compound is 1-methyl-5-mercapto-1H-tetrazole.
25. A process for the preparation of sodium 7.beta.-[.alpha.-methoxyimino-.alpha.-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate which comprises reacting 7.beta.-[.alpha.-methoxyimino-.alpha.-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid with 1-methyl-5-mercapto-1H-tetrazole sodium salt.
26. A process for the preparation of 7.beta.-[.alpha.-methoxyimino-.alpha.-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid sodium salt which comprises reacting 7-aminocephalosporanic acid with .alpha.-methoxyimino-.alpha.-[2-(chloroacetamido)thiazol-4-yl]acetyl chloride, removing the protective chloroacetyl group by reaction with thiourea to produce 7.beta.-[.alpha.-methoxyimino-.alpha.-(2-aminothiazol-4-yl) acetamido]-cephalosporanic acid, and reacting the product with sodium bicarbonate.
27. A process for the preparation of 7.beta.-[.alpha.-(2-aminothi-azol-4-yl)-.alpha.-methoxyiminoacetamido]-3-desacetylcephalosporanic acid sodium salt which comprises reacting .alpha.-methoxyimino-.alpha.-[2-(chloroacetamido)thiazol-4-yl]acetyl chloride with 7-amino-3-desacetylcephalosporanic acid, removing the protective chloro-acetyl group by reaction with thiourea to produce 7.beta.-[.alpha.-methoxy-imino-.alpha.-(2-aminothiazol-4-yl)-acetamido]-3-desacetylcephalo-sporanic acid, and reacting the product with sodium bicarbonate.
28. A process as claimed in claim 7 or 8 wherein R? is a hydroxyl or lower alkoxy group.
29. A process according to Claim 7 or 8 wherein the syn form of the starting material is employed.
30. A process according to Claim 7 or 8 wherein the anti form of the starting material is employed.
31. A process according to claim 7 or 8 wherein the syn form of the starting material is employed and where the protected hydroxyl group is a lower alkoxy group and the acyloxy group is an acetoxy group.
32. A process according to Claim 7 or 8 wherein the anti form of the starting material is employed and where the protected hydroxyl group is a lower alkoxy group and the acyloxy group is an acetoxy group.
33. A process according to Claim 10 wherein the syn form of the starting material is employed.
34. A process according to Claim 10 wherein the anti form of the starting material is employed.
35. A process according to Claim 11 wherein the syn form of the starting material is employed.
36. A process according to Claim 11 wherein the anti form of the starting material is employed.
37. A process for the preparation of a cephalosporin of the formula, wherein R1 represents amino or protected amino group, R5 represents hydroxyl or protected hydroxyl group, R4 represents hydrogen, hydroxyl, acyloxy, carbamoyloxy, thiadiazolylthio, triazolylthio or tetrazolylthio group which may be substituted with lower alkyl group, or a pharmaceutically acceptable salt or ester thereof, which comprises 1) reacting a compound of the formula:
wherein R4 is as defined above, or a salt or ester thereof, with a compound of the formula:
wherein R1 and R5 are as defined above, or a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or 2) reacting a compound of the formula:
wherein R1 and R5 are as defined above, R6 represents acyloxy, carbamoyloxy or a halogen atom, or a salt or ester thereof, with a compound of the formula: R4'-H wherein R4' represents hydroxyl, thiadiazolylthio, triazolylthio or tetrazolylthio group which may be substituted with lower alkyl group, followed by, if necessary, removal of any protective groups; and where required converting any free carboxylic acid of formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or ester of a compound of formula (I) into the free carb-oxylic acid.
wherein R4 is as defined above, or a salt or ester thereof, with a compound of the formula:
wherein R1 and R5 are as defined above, or a salt or reactive derivative thereof, followed by, if necessary, removal of any protective groups; or 2) reacting a compound of the formula:
wherein R1 and R5 are as defined above, R6 represents acyloxy, carbamoyloxy or a halogen atom, or a salt or ester thereof, with a compound of the formula: R4'-H wherein R4' represents hydroxyl, thiadiazolylthio, triazolylthio or tetrazolylthio group which may be substituted with lower alkyl group, followed by, if necessary, removal of any protective groups; and where required converting any free carboxylic acid of formula (I) into a pharmaceutically acceptable salt or ester thereof, or a salt or ester of a compound of formula (I) into the free carb-oxylic acid.
38. A process for the preparation of a cephalosporin of the formula (XXIV) or a pharmaceutically acceptable salt or ester thereof, which comprises reacting an acid of the formula wherein the amino group is optionally protected or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula or a salt or ester thereof, and if desired, converting the acid of formula(XXIV) into a pharmaceutically acceptable salt or ester thereof.
39. A compound of the formula (XXIV) or a pharmaceut-ically acceptable salt or ester thereof whenever prepared by the process of claim 38.
40. A process for the preparation of a cephalosporin of the formula (XXV) or a pharmaceutically acceptable salt or ester thereof, which comprises reacting an acid of the formula wherein the amino group is optionally protected, or a reactive derivative thereof, with 7-aminocephalosporanic acid or a salt or ester thereof, and if desired, converting the acid of formula (XXV) into a pharmaceutically acceptable salt or ester thereof.
41. A compound of the formula (XXV) or a pharmaceutic-ally acceptable salt or ester thereof whenever prepared by the process of claim 40.
42. A process for the preparation of a cephalosporin of the formula (XXVI) or a pharmaceutically acceptable salt or ester thereof, wherein A represent H, acyloxy or carbamoyloxy, with the proviso that A
is not acetoxy, which comprises reacting an acid of the formula wherein the amino and the hydroxy groups are optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula wherein A is as defined above, or a salt or ester thereof, and if desired, converting the acid of formula (XXVI) into a pharmaceutically acceptable acid or ester thereof.
is not acetoxy, which comprises reacting an acid of the formula wherein the amino and the hydroxy groups are optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula wherein A is as defined above, or a salt or ester thereof, and if desired, converting the acid of formula (XXVI) into a pharmaceutically acceptable acid or ester thereof.
43. A compound of the formula (XXVI) or a pharmaceut-ically acceptable salt or ester thereof whenever prepared by the process of claim 42.
44. A process for the preparation of a cephalosporin of the formula (XXVII) or a pharmaceutically acceptable salt or ester thereof, wherein R represents thiadiazolylthio, triazolylthio or a tetrazolylthio group which may be substituted with a lower alkyl group which comprises reacting an acid for the formula wherein the amino and the hydroxy groups are optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula wherein R is as defined above, or a salt or ester thereof, and if desired, converting the acid of formula (XXVII) into a pharmaceutically acceptable salt or ester thereof.
45. A compound of the formula (XXVII) or a pharmaceut-ically acceptable salt or ester thereof whenever prepared by the process of claim 44.
46. A process for the preparation of a cephalosporin of the formula (XXVII) or a pharmaceutically acceptable salt or ester thereof, wherein R represents thiadiazolylthio, triazolylthio or tetrazolylthio group which may be substituted with a lower alkyl group, which comprises reacting a compound of the formula or a salt or ester thereof, wherein the amino and the hydroxy group are optionally protected and Y is a leaving group dis-placeable by the residue (-R) of a compound of the formula HR, with a compound of the formula HR
wherein R is as dfined above, and if desired, converting the acid of formula (XXVII) into a pharmaceutically acceptable salt or ester thereof.
wherein R is as dfined above, and if desired, converting the acid of formula (XXVII) into a pharmaceutically acceptable salt or ester thereof.
47. A compound of the formula (XXVII) or a pharmaceut-ically acceptable salt or ester thereof whenever prepared by the process of claim 46.
48. A process for the preparation of a cephalosporin compound of the formula:
(XXI-a) wherein R1 represents an amino or protected amino group, R5 represents a hydroxyl or protected hydroxyl group, R4 represents i) hydrogen, ii) hydroxyl, iii) mer-capto, iv) cyano, v) azido, vi) amino, vii)car-bamoyloxy, viii) carbamoylthio, ix)thiocarbamoyl-oxy, x) any group of ii), iii), vi) to ix) sub-stituted with lower alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulfonyloxy, xvi) (cis-1,2-epoxypropyl)phosphono or xvii) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, or a pharmaceutically acceptable salt of the acid (XXI-a) or a pharmaceutically acceptable ester of the acid (XXI-a), which process comprises:
(1) reacting a compound of the formula:
(VI-a) wherein R4 is as defined above, or a salt or ester of the compound (VI-a), with a compound of the formula:
(V-a) wherein R1 and R5 are as defined above, or a reactive derivative of the acid (V-a), and where neces-sary, removing the amino-protecting group which may be present in the radical R1 of the obtained product to give a compound of formula (XXI-a) wherein R1 is an amino group, or (2) reacting a compound of the formula:
(IX-a) wherein R6 represents an acyloxy or carbamoyloxy group or a halogen atom, and R1 and R5 are as defined above, or a salt or ester of the compound (IX-a), with a tertiary amine or a compound of the formula: R4'-H wherein R4' repres-ents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, and where required, removing the amino-protecting group which may be present in the radical R1 in the obtained compound to give a compound of formula (XXI-a) wherein R1 is an amino group, and if desired, converting any free carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into a pharmaceutically acceptable salt or ester thereof, or convert-ing any salt or ester of the carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into the free acid or into a pharmaceutically acceptable salt or ester thereof.
(XXI-a) wherein R1 represents an amino or protected amino group, R5 represents a hydroxyl or protected hydroxyl group, R4 represents i) hydrogen, ii) hydroxyl, iii) mer-capto, iv) cyano, v) azido, vi) amino, vii)car-bamoyloxy, viii) carbamoylthio, ix)thiocarbamoyl-oxy, x) any group of ii), iii), vi) to ix) sub-stituted with lower alkyl, xi) acyloxy, xii) a tertiary ammonium group, xiii) hydroxyphenyl, xiv) sulfamoyloxy, xv) alkylsulfonyloxy, xvi) (cis-1,2-epoxypropyl)phosphono or xvii) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, or a pharmaceutically acceptable salt of the acid (XXI-a) or a pharmaceutically acceptable ester of the acid (XXI-a), which process comprises:
(1) reacting a compound of the formula:
(VI-a) wherein R4 is as defined above, or a salt or ester of the compound (VI-a), with a compound of the formula:
(V-a) wherein R1 and R5 are as defined above, or a reactive derivative of the acid (V-a), and where neces-sary, removing the amino-protecting group which may be present in the radical R1 of the obtained product to give a compound of formula (XXI-a) wherein R1 is an amino group, or (2) reacting a compound of the formula:
(IX-a) wherein R6 represents an acyloxy or carbamoyloxy group or a halogen atom, and R1 and R5 are as defined above, or a salt or ester of the compound (IX-a), with a tertiary amine or a compound of the formula: R4'-H wherein R4' repres-ents any of the radicals as defined for R4 except hydrogen, carbamoyloxy, acyloxy and a tertiary ammonium, and where required, removing the amino-protecting group which may be present in the radical R1 in the obtained compound to give a compound of formula (XXI-a) wherein R1 is an amino group, and if desired, converting any free carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into a pharmaceutically acceptable salt or ester thereof, or convert-ing any salt or ester of the carboxylic acid of formula (XXI-a) obtained by process variant 1) or 2) into the free acid or into a pharmaceutically acceptable salt or ester thereof.
49. A process according to claim 48, wherein the starting material of formula (IX-a) of process variant (2) is prepared by reacting a carboxylic acid of formula (V-a) as defined in claim 48 or a reactive derivative of the acid (V-a), with a compound of the formula:
wherein R6 is as defined in claim 48, or a salt or ester of the compound (VI-a-1), and where neces-sary, removing the amino-protecting group which may be present in the radical R1 of the obtained product.
wherein R6 is as defined in claim 48, or a salt or ester of the compound (VI-a-1), and where neces-sary, removing the amino-protecting group which may be present in the radical R1 of the obtained product.
50. A process according to claim 48(1), wherein in formu-lae (V-a) and (XXI-a), R5 is a lower alkoxy group.
51. A process according to claim 49, wherein in formula (V-a), R5 is a lower alkoxy group.
52. A process according to claim 48(1) wherein in the starting material of formula (V-a) the radical R1 is an amino group protected by an amino-protecting group selected from the group consisting of proton, formyl, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkoxyalkylcarbon-yl group, a halo-substituted lower alkoxycarbonyl,a halo-sub-stituted lower alkylcarbonyl group, and an aralkyloxycarbonyl group which may be substituted by nitro, and after the conden-sation reaction, the amino-protecting group is removed to give a compound of formula (XXI-a) wherein R1 is an amino group.
53. A process according to claim 49, wherein in the starting material of formula (V-a) the radical R1 is an amino group protected by an amino-protecting group selected from the group consisting of proton, formyl, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkoxyalkylcarbon-yl group, a halo-substituted lower alkoxycarbonyl, a halo-sub-stituted lower alkylcarbonyl group, and an aralkyloxycarbonyl group, which may be substituted by nitro.
54. A process according to claim 48(1), wherein a reactive derivative of the compound of formula (V-a) is employed, the reactive derivative being selected from the group consisting of acid halide, acid anhydride, mixed acid anhydride, active amide and active ester.
55. A process according to claim 49, wherein a reactive derivative of the compound of formula (V-a) is employed, the reactive derivative being selected from the group consisting of acid halide, acid anhydride, mixed acid anhydride, active amide and active ester.
56. A process according to claim 48(1), wherein a reactive derivative of the compound of formula (V-a) is em-ployed, the reactive derivative being acid chloride or acid bromide.
57. A process according to claim 49,wherein a reactive derivative of the compound of formula (V-a) is employed, the reactive derivative being acid chloride or acid bromide.
58. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents i) hydrogen, ii) hydroxy, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) car-bamoyloxy, viii) carbamoylthio, ix) thiocarbamoyloxy, x)lower alkoxy, lower alkylthio, mono- or di(lower alkyl)amino, mono-or di(lower alkyl)carbamoyloxy, mono- or di(lower alkyl)car-bamoylthio or mono- or di(lower alkyl)thiocarbamoyloxy, xi) acetyloxy, propionyloxy, butyryloxy, benzoyloxy, p-chlorobenzoyloxy or p-methylbenzoyloxy, xii) a tertiary ammonium group selected from the group consisting of pyri-dinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloro-pyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-car-bamoylpyridinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbomethoxycarbamoyl)pyridinium, 4-(N-cyanocarbamoyl)-pyridinium, 4-(carboxymethyl)pyridinium, 4-(hydroxymethyl)-pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium and lutidium, xiii) hydroxyphenyl, xiv) sul-famoyloxy, xv) lower alkylsulfonyloxy, xvi) (cis-1,2-epoxy-propyl)phosphono or xvii) a group of the formula -S-R
wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyri-midyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imida-zolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl amino, mercapto, hydroxy, carbamoyl or carboxyl.
wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyri-midyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imida-zolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl amino, mercapto, hydroxy, carbamoyl or carboxyl.
59. A process according to claim 53, 55 or 57, wherein for preparing a compound of formula (XXI-a) wherein R4 repres-ents i) hydroxy, ii) mercapto, iii) cyano, iv) azido, v) amino, vi) carbamoylthio, vii) thiocarbamoyloxy, viii) lower alkoxy, lower alkylthio, mono- or di(lower alkyl)amino, mono- or di-(lower alkyl)carbamoyloxy, mono- or di(lower alkyl)carbamoyl-thio or mono- or di(lower alkyl) thiocarbamoyloxy, ix) a ter-tiary ammonium group selected from the group consisting of pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloro-pyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoyl-pyridinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbo-methoxycarbamoyl)pyridinium, 4-(N-cyanocarbamoyl)pyridinium, 4-(carboxymethyl)pyridinium, 4-(hydroxymethyl)pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium and lutidium, x) hydroxyphenyl, xi) sulfamoyloxy, xii) lower alkyl-sulfonyloxy, xiii) (cis-1,2-epoxypropyl)phosphono or xiv) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxa-diazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl,lower alkoxy, halogen, halo- sub-stituted lower alkylamino, mercapto, hydroxy, carbamoyl or carboxyl, a compound of formula (IX-a) is reacted with a ter-tiary amine corresponding to the tertiary ammonium group as defined above or a compound of the formula: R4'-H wherein R4' represents any of the radicals as defined above for R4 except for the tertiary ammonium group.
60. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents hydrogen, hydroxyl, acetoxy, lower alkoxy or carbamoyloxy.
61. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxyl, carbamoyl or carboxyl.
wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxyl, carbamoyl or carboxyl.
62. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents an aromatic tertiary ammo-nium group.
63. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
64. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a tertiary ammonium group selected from the group consisting of pyridinium, 3-methyl-pyridinium, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoylpyridinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbomethoxy-carbamoyl)pyridinium, 4-(N-cyanocarbamoyl)pyridinium, 4-(carboxymethyl)pyridinium, 4-(hydroxymethyl)pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium and lutidium.
65. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a pyridinium group.
66. A process according to claim 48(1), wherein in formula (VI-a) R5 represents a pyridinium group.
67. A process according to claim 50, wherein in for-mula (VI-a) R4 represents a pyridinium group.
68. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 6-membered hetero ring containing three nitrogen atoms.
wherein R is a 6-membered hetero ring containing three nitrogen atoms.
69. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5-membered hetero ring containing one nitro-gen atom and one sulfur atom.
wherein R is a 5-membered hetero ring containing one nitro-gen atom and one sulfur atom.
70. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5-membered hetero ring containing three nitro-gen atoms.
wherein R is a 5-membered hetero ring containing three nitro-gen atoms.
71. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5-membered hetero ring containing one sulfur atom and two nitrogen atoms.
wherein R is a 5-membered hetero ring containing one sulfur atom and two nitrogen atoms.
72. A process according to claim 52, 54 or 56, wherein in formula (VI-a) R4 represents a 5-membered hetero ring con-taining four nitrogen atoms.
73. A process according to claim 53, 55 or 57 wherein the nucleophilic compound is a tertiary amine or a mercapto compound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.
74. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is an aromatic tertiary amine.
75. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto com-pound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
76. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto com-pound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
77. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto com-pound of the formula H-S-R or an alkali metal salt thereof wherein R is a 6-membered hetero ring containing three nitrogen atoms.
78. A process according to claim 53, 55, or 57, wherein R6 in formula (VI-a-1) is a carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto com-pound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5-membered hetero ring containing one nitro-gen atom and one sulfur atom.
79. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto com-pound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5-membered hetero ring containing three nitro-gen atoms.
80. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto compound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5-membered hetero ring containing one sulfur atom and two nitrogen atoms.
81. A process according to claim 53, 55 or 57, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine and the nucleophilic compound is a mercapto compound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5-membered hetero ring containing four nitrogen atoms.
82. A process according to claim 48(1), wherein in formula (V-a) and (XXI-a), R5 is a methoxy group.
83. A process according to claim 49, wherein in for-mula (V-a), R5 is a methoxy group.
84. A process according to claim 82, wherein the syn form of the starting material of formula (V-a) is employed.
85. A process according to claim 82, wherein the anti form of the starting material of formula (V-a) is employed.
86. A process according to claim 83, wherein the syn form of the compound of formula (IX-a) is employed.
87. A process according to claim 83, wherein the anti form of the compound of formula (IX-a) is employed.
88. A process according to claim 52, wherein in the starting material of formula (V-a), the radical R1 is protected by a amino-protecting group selected from the group consisting of a lower alkoxycarbonyl group, a halo-substituted lower alkylcarbonyl group, and an aralkyloxycarbonyl group which may be substituted by nitro, and after the condensation reaction, the amino-protecting group is removed to give a compound of formula (XXI-a) wherein R1 is an amino group.
89. A process according to claim 88, wherein a reactive derivative of the compound of formula (V-a) is employed, the reactive derivative being selected from the group consisting of acid halide, acid anhydride, mixed acid anhydride, active amide and active ester.
90. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents i) hydrogen, ii) hydroxy, iii) mercapto, iv) cyano, v) azido, vi) amino, vii) carbamoyloxy, viii) carbamoylthio, ix) thiocarbamoyloxy, x) lower alkoxy, lower alkylthio, mono- or di(lower alkyl)amino, mono- or di-(lower alkyl)carbamoyloxy, mono- or di(lower alkyl)caxbamoyl-thio or mono- or di(lower alkyl)thiocarbamoyloxy, xi) acetyl-oxy, propionyloxy, butyryloxy, benzoyloxy, p-chlorobenzoyloxy or p-methylbenzoyloxy, xii) a tertiary ammonium group selected from the group consisting of pyridi-nium, 3-methylpyridinium, 4-methylpyridinium, 3-chloropyri-dinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoylpyri-dinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbo-methoxycarbamoyl)pyridinium, 4-(N-cyanocarbamoyl)pyridinium, 4-(carboxymethyl)pyridinium, 4-(hydroxymethyl)pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium and lutidium, xiii) hydroxyphenyl,, xiv) sulfamoyloxy, xv) lower alkylsulfonyloxy, xvi) (cis-1,2-epoxypropyl)phosphono or xvii) a group of the formula -S-R wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thia-diazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-tria-zolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
91. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-sub-stituted lower alkyl, amino, mercapto, hydroxyl, carbamoyl or carboxyl.
wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-sub-stituted lower alkyl, amino, mercapto, hydroxyl, carbamoyl or carboxyl.
92. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents an aromatic tertiary ammonium group.
93. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a pyridinium group.
94. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is a 6-membered hetero ring containing three nitro-gen atoms.
wherein R is a 6-membered hetero ring containing three nitro-gen atoms.
95. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is thiazolyl.
wherein R is thiazolyl.
96. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is 1,2,3-triazolyl or 1,2,4-triazolyl.
wherein R is 1,2,3-triazolyl or 1,2,4-triazolyl.
97. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl.
wherein R is 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl.
98. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents a group of the formula -S-R
wherein R is 1H-tetrazolyl or 2H-tetrazolyl.
wherein R is 1H-tetrazolyl or 2H-tetrazolyl.
99. A process according to claim 82, 88 or 89, wherein in formula (VI-a) R4 represents hydrogen, hydroxyl, acetoxy, lower alkoxy, or carbamoyloxy.
100. A process according to claim 83, wherein R6 in formula (VI-a-1) is carbamoyloxy, acetoxy, chlorine or bromine.
101. A process according to claim 83 or 100, wherein the nucleophilic compound is a tertiary amine or a mercapto compound of the formula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.
102. A process according to claim 83 or 100, wherein the nucleophilic compound is an aromatic tertiary amine.
103. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
104. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is a 5- or 6-membered hetero ring selected from the group consisting of pyridyl, N-oxido-pyridyl, pyrimidyl, pyrida-zinyl, N-oxido-pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl and 2H-tetrazolyl, wherein the 5- or 6-membered hetero ring may be substituted by lower alkyl, lower alkoxy, halogen, halo-substituted lower alkyl, amino, mercapto, hydroxy, carbamoyl or carboxyl.
105. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is a 6-membered hetero ring containing three nitrogen atoms.
106. A process according to claim 83 or 1000, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is 1,2,3-triazolyl or 1,2,4-triazolyl.
107. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is 1,2,3-triadiazolyl, 1,2,4-triadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl.
108. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is 1H-tetrazolyl or 2H-tetrazolyl.
109. A process according to claim 83 or 100, wherein the nucleophilic compound is a mercapto compound of the for-mula H-S-R or an alkali metal salt thereof wherein R is pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl or N-oxido-pyridazinyl.
110. A process according to claim 82 or 89, wherein an ester of the compound of formula (VI-a) is employed or a compound of formula (XXI-a) obtained is converted to an ester thereof, the resulting ester being pharmaceutically acceptable and being selected from the group consisting of lower alkoxymethyl, .alpha.-(lower alkoxy)ethyl, lower alkylthio-methyl, lower acyloxymethyl, and .alpha.-(lower acyloxy)-.alpha.-(lower alkyl)methyl esters.
111. A process according to claim 82 or 89, wherein pivaloyloxymethyl ester of the compound of formula (VI-a) is employed or a compound of formula (XXI-a) obtained is converted to pivaloyloxymethyl ester thereof.
112. A process according to claim 83 or 100, wherein an ester of the compound (IX-a) is employed or a compound of formula (XXI-a) obtained is converted to an ester thereof, the resulting ester being pharmaceutically acceptable and being selected from the group consisting of lower alkoxy-methyl, .alpha.-(lower alkoxy)ethyl, lower alkylthiomethyl, lower acyloxymethyl, and .alpha.-(lower acyloxy)-.alpha.-(lower alkyl)methyl esters.
113. A process according to claim 83 or 100, wherein pivaloyloxymethyl ester of the compound of formula (IX-a) is employed or a compound of formula (XXI-a) obtained is converted to pivaloyloxymethyl ester thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP146567/1974 | 1974-12-19 | ||
| JP49146567A JPS5760345B2 (en) | 1974-12-19 | 1974-12-19 | |
| GB24611/75A GB1536281A (en) | 1975-06-09 | 1975-06-09 | Cephem compounds |
| GB24611/75 | 1975-06-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1216284A true CA1216284A (en) | 1987-01-06 |
Family
ID=26257200
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000242004A Expired CA1216284A (en) | 1974-12-19 | 1975-12-18 | Thiazolylacetamido compounds |
| CA315,025A Expired CA1128957A (en) | 1974-12-19 | 1978-10-31 | .alpha.-PROTECTED OXYIMINO-.beta.-OXO-.gamma.-HALOGENOBUTYRIC ACID DERIVATIVES |
| CA000315026A Expired CA1137492A (en) | 1974-12-19 | 1978-10-31 | Thiazolylacetic acid compounds |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA315,025A Expired CA1128957A (en) | 1974-12-19 | 1978-10-31 | .alpha.-PROTECTED OXYIMINO-.beta.-OXO-.gamma.-HALOGENOBUTYRIC ACID DERIVATIVES |
| CA000315026A Expired CA1137492A (en) | 1974-12-19 | 1978-10-31 | Thiazolylacetic acid compounds |
Country Status (18)
| Country | Link |
|---|---|
| US (6) | US4098888A (en) |
| AT (1) | AT357521B (en) |
| AU (1) | AU500104B2 (en) |
| BE (1) | BE836813A (en) |
| BG (1) | BG60437B2 (en) |
| CA (3) | CA1216284A (en) |
| CH (4) | CH624119A5 (en) |
| DE (3) | DE2556736C2 (en) |
| DK (2) | DK154939C (en) |
| ES (4) | ES443627A1 (en) |
| FR (4) | FR2294690A1 (en) |
| GB (1) | GB1536283A (en) |
| HU (1) | HU179798B (en) |
| MX (1) | MX5097E (en) |
| NL (4) | NL183703C (en) |
| NO (1) | NO157933C (en) |
| PH (2) | PH13731A (en) |
| SE (2) | SE442202B (en) |
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1975
- 1975-12-04 DK DK548875A patent/DK154939C/en not_active IP Right Cessation
- 1975-12-15 PH PH17868A patent/PH13731A/en unknown
- 1975-12-17 DE DE2556736A patent/DE2556736C2/en not_active Expired
- 1975-12-17 NO NO754296A patent/NO157933C/en unknown
- 1975-12-17 FR FR7538703A patent/FR2294690A1/en active Granted
- 1975-12-17 SE SE7514286A patent/SE442202B/en not_active IP Right Cessation
- 1975-12-17 MX MX752873U patent/MX5097E/en unknown
- 1975-12-17 DE DE2560398A patent/DE2560398C2/en not_active Expired
- 1975-12-17 GB GB28892/78A patent/GB1536283A/en not_active Expired
- 1975-12-17 DE DE2559942A patent/DE2559942C2/en not_active Expired
- 1975-12-17 HU HU75TA1464A patent/HU179798B/en unknown
- 1975-12-18 BE BE162887A patent/BE836813A/en not_active IP Right Cessation
- 1975-12-18 AU AU87667/75A patent/AU500104B2/en not_active Expired
- 1975-12-18 ES ES443627A patent/ES443627A1/en not_active Expired
- 1975-12-18 NL NLAANVRAGE7514811,A patent/NL183703C/en active Protection Beyond IP Right Term
- 1975-12-18 CA CA000242004A patent/CA1216284A/en not_active Expired
- 1975-12-19 US US05/642,356 patent/US4098888A/en not_active Expired - Lifetime
- 1975-12-19 CH CH1655675A patent/CH624119A5/de not_active IP Right Cessation
-
1976
- 1976-11-29 FR FR7635966A patent/FR2357552A1/en not_active Withdrawn
-
1977
- 1977-04-16 ES ES457891A patent/ES457891A1/en not_active Expired
- 1977-07-12 PH PH19987A patent/PH14161A/en unknown
- 1977-07-18 AT AT517277A patent/AT357521B/en not_active IP Right Cessation
- 1977-11-28 CH CH1451477A patent/CH631437A5/en not_active IP Right Cessation
- 1977-12-06 ES ES464771A patent/ES464771A1/en not_active Expired
- 1977-12-06 ES ES464772A patent/ES464772A1/en not_active Expired
- 1977-12-09 DK DK552377A patent/DK155086C/en active
-
1978
- 1978-01-18 US US05/870,932 patent/US4205180A/en not_active Expired - Lifetime
- 1978-01-20 NL NL7800731A patent/NL7800731A/en not_active Application Discontinuation
- 1978-10-31 CA CA315,025A patent/CA1128957A/en not_active Expired
- 1978-10-31 CA CA000315026A patent/CA1137492A/en not_active Expired
-
1979
- 1979-04-03 SE SE7902954A patent/SE445454B/en not_active IP Right Cessation
- 1979-05-11 FR FR7912111A patent/FR2434146A1/en active Granted
- 1979-09-28 FR FR7924297A patent/FR2468599B1/en not_active Expired
-
1980
- 1980-05-23 CH CH407680A patent/CH633544A5/en not_active IP Right Cessation
- 1980-05-23 CH CH407580A patent/CH628058A5/en not_active IP Right Cessation
- 1980-05-27 NL NL8003054A patent/NL8003054A/en active Search and Examination
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1983
- 1983-06-24 US US06/525,663 patent/US4514565A/en not_active Expired - Lifetime
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1988
- 1988-06-07 US US07/203,409 patent/US4912212A/en not_active Expired - Fee Related
- 1988-06-07 US US07/203,410 patent/US4973684A/en not_active Expired - Fee Related
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1990
- 1990-01-08 US US07/462,492 patent/US5583216A/en not_active Expired - Lifetime
-
1994
- 1994-02-11 BG BG098461A patent/BG60437B2/en unknown
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1995
- 1995-08-22 NL NL950016C patent/NL950016I1/en unknown
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